Bile-acid conjugates for providing sustained systemic concentrations of drugs

ABSTRACT

This invention is directed to compounds that provide for sustained systemic concentrations of therapeutic or prophylactic agents following administration to animals. This invention is also directed to pharmaceutical compositions including and methods using such compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.Nos. 60/238,758, filed Oct. 6, 2000, 60/249,804, filed Nov. 17, 2000,and 60/297,472, filed Jun. 11, 2001, all of which are incorporated byreference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to compounds that provide for sustainedsystemic concentrations of therapeutic or prophylactic agents followingadministration to animals. This invention is also directed topharmaceutical compositions including and methods using such compounds.

2. State of the Art

Rapid clearance of drugs from the systemic circulation represents amajor impediment to effective clinical use of therapeutic and/orprophylactic compounds. Although multiple factors can influence thesystemic concentrations of drugs achieved following administration(including drug solubility, dissolution rate, first-pass metabolism,p-glycoprotein and related efflux mechanisms, hepatic/renal elimination,etc), rapid systemic clearance is a particularly significant reason forsuboptimal systemic exposure to many compounds. Rapid systemic clearancemay require that large doses of drug be administered to achieve atherapeutic or prophylatic effect. Such larger doses of the drug,however, may result in greater variability in drug exposure, morefrequent occurrence of side effects, or decrease in patient compliance.Frequent drug administration may also be required to maintain systemicdrug levels above a minimum effective concentration. This problem isparticularly significant for drugs that must be maintained in a welldefined concentration window to provide continuous therapeutic orprophylactic benefit while minimizing adverse effects (including forexample, antibacterial agents, antiviral agents, anticancer agents,anticonvulsants, anticoagulants, etc.).

Conventional approaches to extend the systemic exposure of drugs withrapid clearance involve the use of formulation or device approaches thatprovide a slow or sustained release of drug within the intestinal lumen.These approaches are well known in the art and normally require that thedrug be well absorbed from the large intestine, where such formulationsare most likely to reside while releasing the drug. Drugs that areamenable to conventional sustained release approaches must be orallyabsorbed in the intestine and traverse this epithelial barrier bypassive diffusion across the apical and basolateral membranes of theintestinal epithelial cells. The physicochemical features of a moleculethat favor its passive uptake from the intestinal lumen into thesystemic circulation include low molecular weight (e.g., <500 Da),adequate solubility, and a balance of hydrophobic and hydrophiliccharacter (logP generally 1.5-4.0) (Navia and Chaturvedi, 1996).

Polar or hydrophilic compounds are typically poorly absorbed through ananimal's intestine as there is a substantial energetic penalty forpassage of such compounds across the lipid bilayers that constitutecellular membranes. Many nutrients that result from the digestion ofingested foodstuffs in animals, such as amino acids, di- andtripeptides, monosaccharides, nucleosides and water-soluble vitamins,are polar compounds whose uptake is essential to the viability of theanimal. For these substances there exist specific mechanisms for activetransport of the solute molecules across the apical membrane of theintestinal epithelia. This transport is frequently energized byco-transport of ions down a concentration gradient. Solute transporterproteins are generally single sub-unit, multi-transmembrane spanningpolypeptides, and upon binding of their substrates are believed toundergo conformational changes which result in movement of thesubstrate(s) across the membrane.

Over the past 10-15 years, it has been found that a number of orallyadministered drugs are recognized as substrates by some of thesetransporter proteins, and that this active transport may largely accountfor the oral absorption of these molecules (Tsuji and Tamai, 1996).While in most instances the transporter substrate properties of thesedrugs were unanticipated discoveries made through retrospectiveanalysis, it has been appreciated that, in principle, one might achievegood intestinal permeability for a drug by designing in recognition anduptake by a nutrient transport system. Drugs subject to activeabsorption in the small intestine are often unable to passively diffuseacross epithelial cell membranes and are too large to pass through thetight junctions that exist between the intestinal cells. These drugsinclude many compounds structurally related to amino acids, dipeptides,sugars, nucleosides, etc. (for example, many cephalosporins, ACEinhibitors, AZT gabapentin, pregabalin, baclofen, etc.)

Rapid systemic clearance occurs in a portion of these drugs and suchclearance requires that they be dosed frequently to maintain atherapeutic or prophylactic concentration in the systemic circulation(Bryans and Wustrow, 1999). Conventional sustained release approacheshave not always been successfully applied to these drugs if they are notabsorbed from the large intestine. Thus there is a significant need foreffective sustained release versions of these drugs, particularly forthe pediatric patient population, since drug must be administered duringschool hours, raising the issues of compliance, liability, and socialacceptance.

One attractive pathway that might be exploitable for sustained deliveryof drugs with rapid systemic clearance is the entero-hepatic circulationof bile acids (Swaan et al, 1996). Bile acids are hydroxylated steroidsthat play a key role in digestion and absorption of fat and lipophilicvitamins. After synthesis in the liver, they are secreted into bile andexcreted by the gall bladder into the intestinal lumen where theyemulsify and help solubilize lipophilic substances. Bile acids areconserved in the body by active uptake from the terminal ileum via thesodium-dependent transporter IBAT (or ASBT) and subsequent hepaticextraction by the transporter NTCP (or LBAT) located in the sinusoidalmembrane of hepatocytes. This efficient mechanism to preserve the bileacid pool is termed the enterohepatic circulation (see FIG. 2). In man,the total bile acid pool (3-5 g) recirculates 6-10 times per day givingrise to a daily uptake of approximately 20-30 g of bile acids.

The high transport capacity of the bile acid pathway has been a keyreason for interest in this system for drug delivery purposes. Severalpapers have postulated that chemical conjugates of bile acids with drugscould be used to provide liver site-directed delivery of a drug to bringabout high therapeutic concentrations in the diseased liver withminimization of general toxic reactions elsewhere in the body; andgallbladder-site delivery systems of cholecystographic agents andcholesterol gallstone dissolution accelerators” (Ho, 1987). Severalgroups have explored these concepts in some detail, using the C-24carboxylic acid, C-3, C-7, and C-12 hydroxyl groups of cholic acid (andother bile acids) as handles for chemically conjugating drugs or drugsurrogates. (Kramer et al, 1992; Kim et al, 1993).

The most rigorous drug targeting studies using the bile acid transportpathway to date relate to work with bile acid conjugates of HMG-CoAreductase inhibitors (Kramer et al, 1994b; Petzinger et al, 1995; Kramerand Wess, 1995; Kramer et al, 1997b). Coupling of the HMG-CoA reductaseinhibitor HR 780 via an amide linkage to the C-3 position of cholate,taurocholate and glycocholate afforded substrates for both the ileal andliver bile acid transporter proteins (FIG. 3). Upon oral dosing of rats,the cholate conjugate S 3554 led to specific inhibition of HMG-CoAreductase in the liver, and in contrast to the parent compound HR 780,gave significantly reduced inhibition of the enzyme in extra-hepaticorgans. Companion studies that looked at the tissue distribution ofradiolabeled drugs two hours after intravenous administration throughthe mesenteric vein of rats also showed dramatically lower systemiclevels for the bile acid conjugate relative to the parent. Becauseinhibition of HMG-CoA reductase requires the presence of the freecarboxylic acid moiety in HR 780 this data was taken to indicate that S3554 served as a prodrug of HR 780, undergoing hydrolysis (and otheruncharacterized metabolism) in the rat liver. Interestingly, uptake of S3554 by liver did not appear to depend on the liver bile acidtransporter NTCP (which prefers taurocholate conjugates), but mayinstead have involved another multispecific organic anion transportsystem on the sinusoidal hepatocyte membrane.

In summary, while the concept of harnessing the intestinal bile aciduptake pathway to enhance the absorption of poorly absorbed drugs iswell appreciated, the existing art has merely demonstrated that bileacid-drug conjugates may be effectively trafficked to the liver andgenerally excreted into the bile, either unchanged or as some type ofmetabolite. The art gives no guidance as to how one prepares acomposition that exploits the bile acid transport pathway andsimultaneously provides therapeutically meaningful levels of a drugsubstance outside of the enterohepatic circulation. Furthermore, the artdoes not describe the potential use of the bile acid transport pathwayto achieve a circulating reservoir of conjugated drug that is slowlyreleased into the systemic circulation to provide sustainedconcentrations.

SUMMARY OF THE INVENTION

This invention is directed to the surprising discovery that the bileacid transport system can be utilized to provide sustained systemicconcentrations of drugs administered to an animal. This invention,therefore, permits sustained therapeutic or prophylactic systemic bloodconcentrations of drugs which heretofore could not be achieved.

Accordingly, in one of its compound aspects, this invention is directedto compounds that provide for sustained therapeutic or prophylacticblood concentrations of a drug or an active metabolite thereof in thesystemic circulation of an animal. Such compounds are of formula (I):

wherein:

R¹ and R² are independently hydrogen or hydroxy;

X is selected from the group consisting of hydroxy and Q^(x)G- where:

G is —O—, —C(O)O— or —N—;

Q^(x) is a group derived from a linear oligopeptide comprising a firstmoiety D and further comprising from 1 to 3 amino acids, and whereinsaid group is cleavable from (I) under physiological conditions;

D is a drug containing at least one carboxylic acid group and at leastone moiety selected from the group consisting of a primary amino group,a secondary amino group or a hydroxyl group, with the provisos that thedrug is not a GABA analog; L-Dopa, an L-aromatic amino aciddecarboxylase inhibitor, a catechol O-methyl transferase inhibitor orderivatives thereof; a naturally occurring α-amino acid or an ester orcarboxamide of a naturally occurring α-amino acid; a polypeptide derivedfrom a linear oligopeptide containing at least 3 α-amino acids; anoligonucleotide; a cyclophane derivative, adiethylenetriaminopentaacetate derivative, or paramagnetic ion chelatesthereof; 5-de-O-methylsporaricin; a bis-(2-chloroethyl)amine containingnitrogen mustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; or a steroid containing the carbon substructures of thefollowing formulae:

Z is selected from the group consisting of:

(i) a substituted alkyl group containing a moiety which is negativelycharged at physiological pH, which moiety is selected from the groupconsisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR⁶)(OH), —OP(O)(OR⁶)(OH),—OSO₃H and the like, and where R⁶ is selected from the group consistingof alkyl, substituted alkyl, aryl and substituted aryl; and

(ii) a group of the formula -M-Q^(x′), wherein M is selected from thegroup consisting of —CH₂OC(O)— and —CH₂CH₂C(O)—, and wherein Q^(x′) is agroup derived from a linear oligopeptide comprising a first moiety D′and further comprising from 1 to 3 amino acids, and wherein said groupis cleavable under physiological conditions;

D′ is a drug containing at least one carboxylic acid group and at leastone moiety selected from the group consisting of a primary amino group,a secondary amino group or a hydroxyl group, with the provisos that thedrug is not a GABA analog; L-Dopa, an L-aromatic amino aciddecarboxylase inhibitor, a catechol O-methyl transferase inhibitor orderivatives thereof; a naturally occurring α-amino acid or an ester orcarboxamide of a naturally occurring α-amino acid; a polypeptide derivedfrom a linear oligopeptide containing at least 3 α-amino acids; anoligonucleotide; a cyclophane derivative, adiethylenetriaminopentaacetate derivative, or paramagnetic ion chelatesthereof; 5-de-O-methylsporaricin; a bis-(2-chloroethyl)amine containingnitrogen mustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; or a steroid containing the carbon substructures of thefollowing formulae:

or a pharmaceutically acceptable salt thereof;

provided that when X is hydroxy, then Z is a group of formula -M-Q^(x′).

Preferably, when X is Q^(x)-G-, Q^(x) is one of the following twostructures:-I_(i)-J_(j)-D-K_(k)—R⁴⁰or-T_(t)-D-U_(u)—V_(v)—R⁴¹

wherein

I is —[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—;

J is —[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—;

K is —[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—;

T is —[C(O)—(CR⁶⁵R⁶⁶)_(g)—(CR⁶⁷R⁶⁸)_(h)—NR⁶⁹]—;

U is —[C(O)—(CR⁷⁰R⁷¹)_(m)—(CR⁷²R⁷³)_(n)—NR⁷⁴]—;

V is —[C(O)—(CR⁷⁵R⁷⁶)_(o)—(CR⁷⁷R⁷⁸)_(p)—NR⁷⁹]—;

R⁴⁰ is —OH or —OR¹⁷;

R⁴¹ is —H, —C(O)R¹⁷, or —C(O)OR¹⁷;

R¹⁷ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl orsubstituted heteroaryl;

a, b, c, d, e, f, g, h, m, n, o and p are independently 0 or 1, whereinat least one of a and b is 1, at least one of c and d is 1, at least oneof e and f is 1, at least one of g and h is 1, at least one of m and nis 1, at least one of o and p is 1;

i, j, k, t, u and v are independently 0 or 1, wherein at least one of i,j and k is 1, and wherein at least one of t, u and v is 1;

R⁵⁰ is hydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring;

R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵⁵ is hydrogen or R⁵⁵ and R⁵⁶, together with the atoms to which theyare attached form a heterocyclyl ring;

R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁸ and R⁵⁹ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁰ is hydrogen or R⁶⁰ and R⁶¹, together with the atoms to which theyare attached form a heterocyclyl ring;

R⁶¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶¹ and R⁶² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶¹ andR⁶³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁶² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶³ and R⁶⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶⁵ and R⁶⁶ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶⁵ andR⁶⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁶⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶⁷ and R⁶⁸ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁶⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁹ is hydrogen or R⁶⁹ and R⁶⁸ together with the atoms to which they areattached form a heterocyclyl ring;

R⁷⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷⁰ and R⁷¹ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁷⁰ andR⁷² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁷¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁷² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷² and R⁷³ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁷³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁷⁴ is hydrogen or R⁷⁴ and R⁷³ together with the atoms to which they areattached form a heterocyclyl ring;

R⁷⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷⁵ and R⁷⁶ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁷⁵ andR⁷⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁷⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁷⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷⁷ and R⁷⁸ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁷⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; and

R⁷⁹ is hydrogen or R⁷⁹ and R⁷⁸ together with the atoms to which they areattached form a heterocyclyl ring;

wherein the bond between J_(j) or U_(u) and D and any amino acid towhich it is attached is an amide or ester bond, and where the bondbetween D and K_(k) or T_(t) is an amide bond.

Preferably, where Z is a substituted alkyl group of the formula-M-Q^(x′), and wherein Q^(x′) is of the following structure:-I′_(i′)-J′_(j′)-D′-K′_(k′)—R^(40′)

wherein

I′ is —[NR^(50′)—(CR^(51′)R^(52′))_(a′)—(CR^(53′)R^(54′))_(b′)—C(O)]—;

J′ is —[NR^(55′)—(CR^(56′)R^(57′))_(c′)—(CR^(58′)R^(59′))_(d′)—C(O)]—;

K′ is —[NR^(60′)—(CR^(61′)R^(62′))_(e′)—(CR^(63′)R^(64′))_(f′)—C(O)]—;

R^(40′) is —OH or —OR^(17′);

R^(17′) is alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

a′, b′, c′, d′, e′ and f′ are independently 0 or 1, wherein at least oneof a′ and b′ is 1, at least one of c′ and d′ is 1, at least one of e′and f′ is 1;

i′, j′ and k′ are independently 0 or 1, wherein at least one of i′, j′and k′ is R^(50′) is hydrogen or R^(50′) and R^(5′) together with theatoms to which they are attached form a heterocyclyl ring;

R^(5′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(5′) and R^(52′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R^(5′) andR^(53′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R^(52′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(53′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(53′) and R^(54′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R^(54′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(55′) is hydrogen or R^(55′) and R^(56′), together with the atoms towhich they are attached form a heterocyclyl ring;

R^(56′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(56′) and R^(57′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R^(56′)and R^(58′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R^(57′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(58′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(58′) and R^(59′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R^(59′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(60′) is hydrogen or R^(60′) and R^(61′), together with the atoms towhich they are attached form a heterocyclyl ring;

R^(6′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(6′) and R^(62′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R^(6′) andR^(63′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R^(62′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(63′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(63′) and R^(64′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R^(64 ′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

wherein the bond between J′_(j′) and D′ and any amino acid to which itis attached is an amide or ester bond.

Preferably, R′ and R² of a compound of formula (I) are both α-OH; R¹ isβ-OH and R² is hydrogen; R¹ is α-OH and R² is hydrogen, R¹ is hydrogenand R² is α-OH; R¹ is α-OH and R² is α-OH; or R¹ and R² are bothhydrogen

When amino acids I, J, K, T, U and V are included in a compound offormula (I), they are typically derived from naturally occurring α-aminoacids.

When amino acids I′, J′ and K′ are included in a compound of formula(I), they are typically derived from naturally occurring α-amino acids.

Preferably, where Q^(x) of a compound of formula (I) is of the structure-I_(i)-J_(j)-D-K_(k)—R⁴⁰ or -T_(t)-D-U_(u)—V_(v)—R⁴¹ then b, c, d, e, f,g, h, j, k, m, n, o and p are 0, and a′ and i′ are 1.

Preferably, where Q^(x′) of a compound of formula (I) is of thestructure -I′_(i)-J′_(j)-D′-K′_(k′—R) ^(40′), then b′, c′, d′, e′ and f′are 0, and a′ is 1.

Preferably, with respect to substituents included in a compound offormula (I), X is hydroxy and Q^(x′) is-I′_(i′)-J′_(j′)-D′-K′_(k′)—R^(40′).

Preferably in the method, where a compound of formula (I) contains thesubstituents R^(50′), R⁵¹′ and R^(52′), the substituents are defined asfollows: R^(50′) is hydrogen, R^(5′) is selected from the groupconsisting of hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl,cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl,2-indolyl, —CH₂OH, —CH(OH)CH₃, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃ orCH₂SH, and R^(52′) is hydrogen.

Another aspect of this invention is a compound of formula (II):

wherein:

R¹ and R² are independently hydrogen or hydroxy;

X is selected from the group consisting of hydroxy and P^(x)-G- where:

G is —O—, —C(O)O— or —NH—;

P^(x) is a group derived from a linear oligopeptide comprising a firstmoiety D″ and further comprising from 1 to 3 amino acids, and whereinsaid group is cleavable from (II) under physiological conditions;

D″ is a drug containing at least one moiety selected from the groupconsisting of a primary amino group, a secondary amino group or ahydroxyl group, with the provisos that the drug is not a GABA analog;L-Dopa, an L-aromatic amino acid decarboxylase inhibitor, a catecholO-methyl transferase inhibitor or derivatives thereof; a naturallyoccurring α-amino acid or an ester or carboxamide of a naturallyoccurring α-amino acid; a polypeptide derived from a linear oligopeptidecontaining at least 3 α-amino acids; an oligonucleotide; a cyclophanederivative, a diethylenetriaminopentaacetate derivative, or paramagneticion chelates thereof; histamine or tyramine; 5-de-O-methylsporaricin; abis-(2-chloroethyl)amine containing nitrogen mustard; an HMG-CoAreductase inhibitor; a proline hydroxylase inhibitor; fluvalinate; or asteroid containing the carbon substructures of the following formulae:

Z is selected from the group consisting of:

(i) a substituted alkyl group containing a moiety which is negativelycharged at physiological pH, which moiety is selected from the groupconsisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR⁶)(OH), —OP(O)(OR⁶)(OH),—OSO₃H and the like, and where R⁶ is selected from the group consistingof alkyl, substituted alkyl, aryl and substituted aryl; and

(ii) a group of the formula -M-P^(x′), wherein M is selected from thegroup consisting of —CH₂OC(O)— and —CH₂CH₂C(O)—, and wherein P^(x′) is agroup derived from a linear oligopeptide comprising a first moiety D′″and further comprising from 1 to 3 amino acids, and wherein said groupis cleavable under physiological conditions;

D′″ is a drug containing at least one moiety selected from the groupconsisting of a primary amino group, a secondary amino group or ahydroxyl group, with the provisos that the drug is not a GABA analog;L-Dopa, an L-aromatic amino acid decarboxylase inhibitor, a catecholO-methyl transferase inhibitor or derivatives thereof; a naturallyoccurring α-amino acid or an ester or carboxamide of a naturallyoccurring α-amino acid; a polypeptide derived from a linear oligopeptidecontaining at least 3 α-amino acids; an oligonucleotide; a cyclophanederivative, a diethylenetriaminopentaacetate derivative, or paramagneticion chelates thereof; histamine or tyramine; 5-de-O-methylsporaricin; abis-(2-chloroethyl)amine containing nitrogen mustard; an HMG-CoAreductase inhibitor; a proline hydroxylase inhibitor; fluvalinate; or asteroid containing the carbon substructures of the following formulae:

or a pharmaceutically acceptable salt thereof;

provided that when X is hydroxy, then Z is a group of formula -M-P^(x′).

Preferably, X is P^(x)-G-, G is —C(O)O—, and P^(x) is of the followingstructure:-I_(i)-J_(j)-K_(k)-D″

wherein

I is —[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—;

J is —[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—;

K is —[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—;

a, b, c, d, e and f are independently 0 or 1, wherein at least one of aand b is 1, at least one of c and d is 1, at least one of e and f is 1;

i, j and k are independently 0 or 1, wherein at least one of i, j and kis 1;

R⁵⁰ is hydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring;

R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵⁵ is hydrogen or R⁵⁵ and R⁵⁶, together with the atoms to which theyare attached form a heterocyclyl ring;

R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁸ and R⁵⁹ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁰ is hydrogen or R⁶⁰ and R⁶¹, together with the atoms to which theyare attached form a heterocyclyl ring;

R⁶¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶¹ and R⁶² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶² andR⁶³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁶² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶³ and R⁶⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

wherein the bond between K_(k) and D″ and any amino acid to which it isattached is an amide or ester bond.

Preferably, where Z is a substituted alkyl group of the formula-M-P^(x), P^(x′) is of the following structure:-I′_(i′)-J′_(j′)-K′_(k′)-D′″

wherein

I′ is —[NR^(50′)—(CR^(51′)R^(52′))_(a′)—(CR^(53′)R^(54′))_(b′)—C(O)]—;

J′ is —[NR^(55′)—(CR^(56′)R^(57′))_(e′)—(CR^(58′)R^(59′))_(d′)—C(O)]—;

K′ is —[NR^(60′)—(CR^(61′)R^(62′))_(e′)—(CR^(63′)R^(64′))_(f′)—C(O)]—;

a′, b′, c′, d′, e′ and f′ are independently 0 or 1, wherein at least oneof a′ and b′ is 1, at least one of c′ and d′ is 1, at least one of e′and f′ is 1;

i′, j′ and k′ are independently 0 or 1, wherein at least one of i′, j′and k′ is 1;

R^(50′) is hydrogen or R^(50′) and R^(51′) together with the atoms towhich they are attached form a heterocyclyl ring;

R^(51′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(51′) and R^(52′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R^(51′)and R^(53′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R^(52′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(53′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(53′) and R^(54′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R^(54′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(55′) is hydrogen or R^(55′) and R^(56′), together with the atoms towhich they are attached form a heterocyclyl ring;

R^(56′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(56′) and R^(5′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R^(56′)and R^(58′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R^(57′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(58′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(58′) and R^(59′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R^(59′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(60′) is hydrogen or R^(60′) and R^(61′), together with the atoms towhich they are attached form a heterocyclyl ring;

R^(6′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(6′) and R^(62′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R^(61′)and R^(63′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R^(62′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(63′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(63′) and R^(64′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R^(64′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

wherein the bond between K′_(k′) and D′″ and any amino acid to which itis attached is an amide or ester bond.

Preferably, R¹ and R² are both α-OH; R¹ is β-OH and R² is hydrogen; R¹is α-OH and R² is hydrogen; R¹ is hydrogen and R² is α-OH; R¹ is β-OHand R² is α-OH; or R¹ and R² are both hydrogen.

When amino acids I, J and K are included in a compound of Formula II,they are typically derived from naturally occurring α-amino acids.

When amino acids I′, J′ and K′ are included in a compound of Formula II,they are typically derived from naturally occurring α-amino acids.

Preferably, where P^(x) of a compound of formula II is of the structure-I_(i)-J_(j)-K_(k)-D″ in Formula II, b, c, d, e, f, j and k are 0, and aand i are 1.

Preferably, where P^(x) of a compound of formula II is of the structure-I′_(i′)-J′_(j)-K′_(k′)-d′″, b′, c′, d′, e′, f′, j′ and k′ are 0, andwherein a′ and i′ 1.

Yet another aspect of this invention is a compound of formula (III):

wherein:

R₁ and R² are independently hydrogen or hydroxy;

X is selected from the group consisting of hydroxy and S^(x)-G- where:

G is —O—, or —NH—;

S^(x) is a group derived from a linear oligopeptide comprising a firstmoiety D* and further comprising from 1 to 3 amino acids, and whereinsaid group is cleavable from (III) under physiological conditions;

D* is a drug containing at least one carboxylic acid group, with theprovisos that the drug is not a GABA analog; L-Dopa, an L-aromatic aminoacid decarboxylase inhibitor, a catechol O-methyl transferase inhibitoror derivatives thereof; a naturally occurring α-amino acid or an esteror carboxamide of a naturally occurring α-amino acid; a polypeptidederived from a linear oligopeptide containing at least 3 α-amino acids;an oligonucleotide; a cyclophane derivative, adiethylenetriaminopentaacetate derivative, or paramagnetic ion chelatesthereof; 5-de-O-methylsporaricin; a bis-(2-chloroethyl)amine containingnitrogen mustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; or a steroid containing the carbon substructures of thefollowing formulae:

Z is selected from the group consisting of:

a substituted alkyl group containing a moiety which is negativelycharged at physiological pH, which moiety is selected from the groupconsisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR⁶)(OH), —OP(O)(OR⁶)(OH),—OSO₃H and the like, and where R⁶ is selected from the group consistingof alkyl, substituted alkyl, aryl and substituted aryl.

Preferably, X is S^(x)-G-, and S^(x) is of the following structure:-T_(t)-U_(u)—V_(v)-D*

wherein:

T is —[C(O)—(CR⁶⁵R⁶⁶)_(g)—(CR⁶⁷R⁶⁸)_(h)—NR⁶⁹]—;

U is —[C(O)—(CR⁷⁰R⁷¹)_(m)—(CR⁷²R⁷³)_(n)—NR⁷⁴]—;

V is —[C(O)—(CR⁷⁵R⁷⁶)_(o)—(CR⁷⁷R⁷⁸)_(p)—NR⁷⁹]—;

g, h, m, n, o and p are independently 0 or 1, wherein at least one of gand h is 1, at least one of m and n is 1, at least one of o and p is 1;

t, u and v are independently 0 or 1, wherein at least one of t, u and vis 1;

R⁶⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶⁵ and R⁶⁶ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶⁵ andR⁶⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁶⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶⁷ and R⁶⁸ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁶⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁹ is hydrogen or R⁶⁹ and R⁶⁸ together with the atoms to which they areattached form a heterocyclyl ring;

R⁷⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷⁰ and R⁷¹ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁷⁰ andR⁷² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁷¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁷² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷² and R⁷³ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁷³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁷⁴ is hydrogen or R⁷⁴ and R⁷³ together with the atoms to which they areattached form a heterocyclyl ring;

R⁷⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷⁵ and R⁷⁶ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁷⁵ andR⁷⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁷⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁷⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷⁷ and R⁷⁸ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁷⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; and

R⁷⁹ is hydrogen or R⁷⁹ and R⁷⁸ together with the atoms to which they areattached form a heterocyclyl ring;

wherein the bond between V_(v) and D* and any amino acid to which it isattached is an amide bond.

Preferably, R¹ and R² of Formula III are both α-OH; R¹ is β-OH and R² ishydrogen; R¹ is α-OH and R² is hydrogen; R¹ is hydrogen and R² is α-OH;R¹ is β-OH and R² is α-OH; or R¹ and R² are both hydrogen.

Preferably, when included in a compound of Formula III, amino acids T, Uand V are derived from naturally occurring α-amino acids.

Preferably, where S^(x) of a compound of formula III is of the structure-T_(t)-U_(u)—V_(v)-D*, then h, m, n, o, p, u and v are 0, and g and tare 1.

In a method aspect of this invention, the compounds of this inventionare preferably used in a method for achieving sustained therapeutic orprophylactic blood concentrations of a drug, or an active metabolitethereof, in the systemic circulation of an animal. The method involvesadministering a compound of formula (I), (II), or (III) to an animal.

In a composition aspect of this invention, the compounds of thisinvention are mixed with a pharmaceutically acceptable carrier toprovide a composition. The composition is preferably used in the methodof achieving sustained therapeutic or prophylactic blood concentrationsof a drug or an active metabolite thereof discussed above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates structural analogs of γ-aminobutyric acid (GABA).

FIG. 2 illustrates the enterohepatic circulation with key transporterproteins identified which mediate bile acid circulation.

FIG. 3 illustrates HMG-CoA reductase inhibitor HR 780 as well asconjugates employing the lactone-opened ring of HR 780 coupled to a bileacid.

FIGS. 4-8 illustrate reaction sequences for preparation of variouscompounds having a GABA analog substitutent, similar to the compounds ofFormula I.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to compounds that provide for sustainedsystemic concentrations of therapeutic or prophylactic drugs followingadministration to animals. This invention is also directed to methodsusing the compounds and pharmaceutical compositions that are used insuch methods. However, prior to describing this invention in furtherdetail, the following terms will first be defined:

Definitions

As used herein, the term “animal” refers to various species such asmammalian and avian species including, by way of example, humans,cattle, sheep, horses, dogs, cats, turkeys, chicken, and the like.Preferably, the animal is a mammal and even more preferably is a human.

“Administering to the animal” refers to delivering a compound of formula(I) to an animal through a suitable route. Such routes include, forexample, oral, rectal, subcutaneous, intravenous, intramuscular andintranasal. Preferably, the compound is orally administered to theanimal.

“Orally delivered drugs” refer to drugs which are administered to ananimal in an oral form, preferably, in a pharmaceutically acceptablediluent. Oral delivery includes ingestion of the drug as well as oralgavage of the drug.

“PEPT1 oligopeptide transporter” refers to a type of protein thatabsorbs peptides in certain tissues, such as the intestine. Thistransporter is described and characterized in the literature. See Adibi,S. A., Gastroenterology 1997, 113, 332-340 and Leibach et al., Ann. Rev.Nutr. 1996, 16, 99-119 for a discussion of the transporter.

“PEPT2 oligopeptide transporter” refers to a type of protein thatabsorbs peptides in certain tissues, such as the kidney. Thistransporter is described and characterized in the literature. See Dieck,S. T. et al., GLIA 1999, 25, 10-20, Leibach et al., Ann. Rev. Nutr.1996, 16, 99-119; and Wong et al., Am. J. Physiol. 1998, 275, C967-C975for a discussion of the transporter.

“Transported by either a PEPT1 or PEPT2 oligopeptide transporter” refersto the translocation of a molecule across a membrane of a cellexpressing the transporter. The translocation occurs through interactionwith the transporter and is energized by cotransport of H⁺ ions acrossthe membrane.

“Amino acid” is intended to denote α-amino acids and β-amino acids only.α-Amino acids are molecules of the formula HNR⁵⁰—CR⁵¹R⁵²—C(O)OH:wherein:

R⁵⁰ is hydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring;

R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring.

β-Amino acids are molecules of formula:HNR⁵⁰—(CR⁵¹R⁵²)—(CR⁵³R⁵⁴)—C(O)OH:wherein:

R⁵⁰ is hydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring;

R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl.

“Naturally occurring amino acid” refers to any of the alpha-amino acidsthat are the chief components of proteins. The amino acids are eithersynthesized by living cells or are obtained as essential components ofthe diet. Such amino acids include, for example, the following: alanine,arginine, asparagines, aspartic acid, cysteine, glutamine, glutamicacid, glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine andvaline.

“Drugs that are either completely or incompletely translocated acrossthe intestinal wall into the systemic blood circulation of an animal”refer to any of the well known orally delivered drugs currentlydelivered by oral administration as well as drugs which cannot be orallyadministered because such drugs are insufficiently translocated acrossthe intestinal wall of an animal to provide therapeutic or prophylacticblood concentrations in said animal.

Preferably, drugs that fall into the following categories:

(i) drugs which are insufficiently translocated across the intestinalwall to provide therapeutic or prophylactic blood concentrations;

(ii) incompletely translocated drugs; or (iii) drugs that are eithercompletely or incompletely translocated across the intestinal wall intothe systemic blood circulation of an animal,

contain suitable functionality to provide points of linkage in formingcompounds of formula (I), (II) and (III) above. Such functionalityincludes, by way of example, carboxyl groups, amine groups and hydroxylgroups.

Examples of drugs containing carboxyl groups include, for instance,angiotensin-converting enzyme inhibitors such as alecapril,1-[4-carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylicacid, enalaprilic acid, lisinopril,N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]glycine,pivopril, quinaprilat, (2R,4R)-2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylicacid, (S) benzamido-4-oxo-6-phenylhexenoyl-2-carboxypyrrolidine,[2S-1[R*(R*))]]2α, 3αβ, 7αβ]-1 [2-[[1-carboxy-3-phenylpropyl]-amino-1-oxopropyl]octahydro-1H-indole-2-carboxylic acid, [3S-1[R*(R*))]],3R*]-2-[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolonecarboxylic acid and tiopronin; cephalosporin antibiotics such ascefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazuflur,cefazolin, cefbuperazone, cefixime, cefme noxime, cefmetazole,cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotefan,cefotiam, cefoxitin, cefpimizole, cefpirome, cefpodoxime, cefroxadine,cefsulodin, cefpiramide, ceftazidime, ceftezole, ceftizoxime,ceftriaxone, cefuroxime, cephacetrile, cephalexin, cephaloglycin,cephaloridine, cephalosporin, cephanone, cephradine and latamoxef;penicillins such as amoxycillin, ampicillin, apalcillin, azidocillin,azlocillin, benzylpencillin, carbenicillin, carfecillin, carindacillin,cloxacillin, cyclacillin, dicloxacillin, epicillin, flucloxacillin,hetacillin, methicillin, mezlocillin, nafcillin, oxacillin,phenethicillin, piperazillin, sulbenicillin, temocillin and ticarcillin;thrombin inhibitors such as argatroban, melagatran and napsagatran;influenza neuraminidase inhibitors such as zanamivir and BCX-1812;non-steroidal antiinflammatory agents such as acametacin, alclofenac,alminoprofen, aspirin (acetylsalicylic acid), 4-biphenylacetic acid,bucloxic acid, carprofen, cinchofen, cinmetacin, clometacin, clonixin,diclenofac, diflunisal, etodolac, fenbufen, fenclofenac, fenclosic acid,fenoprofen, ferobufen, flufenamic acid, flufenisal, flurbiprofin,fluprofen, flutiazin, ibufenac, ibuprofen, indomethacin, indoprofen,ketoprofen, ketorolac, lonazolac, loxoprofen, meclofenamic acid,mefenamic acid,2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid,naproxen, nifluminic acid, O-(carbamoylphenoxy)acetic acid, oxoprozin,pirprofen, prodolic acid, salicylic acid, salicylsalicylic acid,sulindac, suprofen, tiaprofenic acid, tolfenamic acid, tolmetin andzopemirac; prostaglandins such as ciprostene,16-deoxy-16-hydroxy-16-vinyl prostaglandin E₂,6,16-dimethylprostaglandin E₂, epoprostostenol, meteneprost, nileprost,prostacyclin, prostaglandins E₁, E₂, or F_(2α) and thromboxane A₂;quinolone antibiotics such as acrosoxacin, cinoxacin, ciprofloxacin,enoxacin, flumequine, naladixic acid, norfloxacin, ofloxacin, oxolinicacid, pefloxacin, pipemidic acid and piromidic acid; other antibioticssuch as aztreonam, imipenem, meropenem and related carbopenemantibiotics.

Representative drugs containing amine groups include: acebutalol,albuterol, alprenolol, atenolol, bunolol, bupropion, butopamine,butoxamine, carbuterol, cartelolol, colterol, deterenol, dexpropanolol,diacetolol, dobutamine, exaprolol, exprenolol, fenoterol, fenyripol,labotolol, levobunolol, metolol, metaproterenol, metoprolol, nadolol,pamatolol, penbutalol, pindolol, pirbuterol, practolol, prenalterol,primidolol, prizidilol, procaterol, propanolol, quinterenol, rimiterol,ritodrine, solotol, soterenol, sulfiniolol, sulfinterol, sulictidil,tazaolol, terbutaline, timolol, tiprenolol, tipridil, tolamolol,thiabendazole, albendazole, albutoin, alendronate, alinidine,alizapride, amiloride, aminorex, aprinocid, cambendazole, cimetidine,cisapride, clonidine, cyclobenzadole, delavirdine, efegatrin,etintidine, fenbendazole, fenmetazole, flubendazole, fludorex,icadronate, lobendazole, mebendazole, metazoline, metoclopramide,methylphenidate, mexiletine, neridronate, nocodazole, oxfendazole,oxibendazole, oxmetidine, pamidronate, parbendazole, pramipexole,prazosin, procainamide, ranitidine, tetrahydrazoline, tiamenidine,tinazoline, tiotidine, tocainide, tolazoline, tramazoline,xylometazoline, dimethoxyphenethylamine,

N-[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1-yl]acetyl-3(R)-methyl-β-alanine,adrenolone, aletamine, amidephrine, amphetamine, aspartame, bamethan,betahistine, clorprenaline, chlortermine, ephrinephrine etryptamine,fenfluramine, methyldopamine, norepinephrine, tocainide, enviroxime,nifedipine, nimodipine, triamterene, norfloxacin and similar compoundssuch as pipedemic acid,1-ethyl-6-fluoro-1,4dihydro-4-oxo-7-(1-piperazinyl)-1,8-napthyridine-3-carboxylicacid,1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazinyl)-3-quinolinecarboxylicacid.

Representative drugs containing hydroxy groups include: steroidalhormones such as allylestrenol, cingestol, dehydroepiandrosteron,dienostrol, diethylstilbestrol, dimethisteron, ethyneron, ethynodiol,estradiol, estron, ethinyl estradiol, ethisteron, lynestrenol,mestranol, methyl testosterone, norethindron, norgestrel, norvinsteron,oxogeston, quinestrol, testosteron and tigestol; tranquilizers such asdofexazepam, hydroxyzin, lorazepam and oxazepam; neuroleptics such asacetophenazine, carphenazine, fluphenazine, perphenyzine andpiperaetazine; cytostatics such as aclarubicin, cytarabine, decitabine,daunorubicin, dihydro-5-azacytidine, doxorubicin, epirubicin,estramustin, etoposide, fludarabine, gemcitabine,7-hydroxychlorpromazin, nelarabine, neplanocin A, pentostatin,podophyllotoxin, tezacitabine, troxacitabine, vinblastin, vincristin,vindesin; hormones and hormone antagonists such as buserilin,gonadoliberin, icatibrant and leuprorelin acetate; antihistamines suchas terphenadine; analgesics such as diflunisal, naproxol, paracetamol,salicylamide and salicyclic acid; antibiotics such as azidamphenicol,azithromycin, camptothecin, cefamandol, chloramphenicol, clarithromycin,clavulanic acid, clindamycin, demeclocyclin, doxycyclin, erythromycin,gentamycin, imipenem, latamoxef, metronidazole, neomycin, novobiocin,oleandomycin, oxytetracyclin, tetracycline, thiamenicol and tobramycin;antivirals such as acyclovir, d4C, ddC, DMDC, Fd4C, FddC, FMAU, FTC,2′-fluoro-ara-dideoxyinosine, ganciclovir, lamivudine, penciclovir,SddC, stavudine, 5-trifluoromethyl-2′-deoxyuridine, zalcitabine andzidovudine; bisphosphonates such as EB-1053, etidronate, ibandronate,olpadronate, residronate, YH-529 and zolendronate; protease inhibitorssuch as ciprokiren, enalkiren, ritonavir, saquinavir and terlakiren;prostaglandins such as arbaprostil, carboprost, misoprostil andprostacydin; antidepressives such as 8-hydroxychlorimipramine and2-hydroxyimipramine; antihypertonics such as sotarol and fenoldopam;anticholinerogenics such as biperidine, procyclidin and trihexyphenidal;antiallergenics such as cromolyn; glucocorticoids such as betamethasone,budenosid, chlorprednison, clobetasol, clobetasone, corticosteron,cortisone, cortodexon, dexamethason, flucortolon, fludrocortisone,flumethasone,flunisolid, fluprednisolon, flurandrenolide, flurandrenolonacetonide, hydrocortisone, meprednisone, methylpresnisolon,paramethasone, prednisolon, prednisol, triamcinolon and triamcinolonacetonide; narcotic agonists and antagonists such as apomorphine,buprenorphine, butorphanol, codein, cyclazocin, hydromorphon,ketobemidon, levallorphan, levorphanol, metazocin, morphine, nalbuphin,nalmefen, naloxon, nalorphine, naltrexon, oxycodon, oxymorphon andpentazocin; stimulants such asmazindol and pseudoephidrine; anaestheticssuch as hydroxydion and propofol; β-receptor blockers such asacebutolol, albuterol, alprenolol, atenolol, betazolol, bucindolol,cartelolol, celiprolol, cetamolol, labetalol, levobunelol, metoprolol,metipranolol, nadolol, oxyprenolol, pindolol, propanolol and timolol;α-sympathomimetics such as adrenalin, metaraminol, midodrin,norfenefrin, octapamine, oxedrin, oxilofrin, oximetazolin andphenylefrin; β-sympathomimetics such as bamethan, clenbuterol,fenoterol, hexoprenalin, isoprenalin, isoxsuprin, orciprenalin,reproterol, salbutamol and terbutalin; bronchodilators such ascarbuterol, dyphillin, etophyllin, fenoterol, pirbuterol, rimiterol andterbutalin; cardiotonics such as digitoxin, dobutamin, etilefrin andprenalterol; antimycotics such as amphotericin B, chlorphenesin,nystatin and perimycin; anticoagulants such as acenocoumarol,dicoumarol, phenprocoumon and warfarin; vasodilators such as bamethan,dipyrimadol, diprophyllin, isoxsuprin, vincamin and xantinol nicotinate;antihypocholesteremics such as compactin, eptastatin, mevinolin andsimvastatin; miscellaneous drugs such as bromperidol (antipsychotic),dithranol (psoriasis) ergotamine (migraine) ivermectin (antihelminthic),metronidazole and secnizadole (antiprotozoals), nandrolon (anabolic),propafenon and quinadine (antiarythimics), quetiapine (CNS), serotonin(neurotransmitter) and silybin (hepatic disturbance).

It is understood that the drug is not a GABA analog; L-Dopa, anL-aromatic amino acid decarboxylase inhibitor, a catechol O-methyltransferase inhibitor or derivatives thereof; a naturally occurringα-amino acid or an ester or carboxamide of a naturally occurring α-aminoacid; a polypeptide derived from a linear oligopeptide containing atleast 3 α-amino acids; an oligonucleotide; a cyclophane derivative, adiethylenetriaminopentaacetate derivative, or paramagnetic ion chelatesthereof; histamine or tyramine; 5-de-O-methylsporaricin; abis-(2-chloroethyl)amine containing nitrogen mustard; an HMG-CoAreductase inhibitor; a proline hydroxylase inhibitor; fluvalinate; or asteroid containing the carbon substructures of the following formulae:

“GABA analog” refers to a compound of one of the following formulae:

wherein:

R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to which they areattached form a heterocyclic ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

R⁹ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

R¹¹ is selected from the group consisting of carboxylic acid, carboxylicamide, carboxylic ester, sulfonamide, phosphonic acid, acidicheterocycle, sulfonic acid and hydroxamic acid;

R^(4′) is hydrogen, or R^(4′) and R^(9′) together with the atoms towhich they are attached form a heterocyclic ring;

R^(5′) and R^(6′) are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

R^(7′) and R^(8′) are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl,substituted aryl, heteroaryl and substituted heteroaryl, or R^(7′) andR^(8′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclic or substitutedheterocyclic ring;

R^(9′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

R^(10′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

R^(11′) is selected from the group consisting of carboxylic acid,carboxylic amide, carboxylic ester, sulfonamide, phosphonic acid, acidicheterocycle, sulfonic acid and hydroxamic acid.

“Catechol O-methyl transferase inhibitor” preferably refers to catecholO-methyl transferase inhibitors such as entacapone, nitecapone andtolcapone optionally with one or two hydrogen atoms of two hydroxylgroups of the catechol group replaced with —C(O)R⁴⁴, —C(O)OR⁴⁵ and/or—OCR⁴³R⁴⁴OC(O)R⁴⁵, wherein R⁴³ and R⁴⁴ independently are membersselected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,aralkyl, substituted aralkyl, heteroaryl and substituted heteroaryl, orR⁴³ and R⁴⁴ together with the carbon atom to which they are attachedform a cycloalkyl, substituted cycloalkyl, heterocycle or substitutedheterocyclic ring, R⁴⁵ is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, aralkyl, substituted aralkyl, heteroaryl and substitutedheteroaryl, or the OH group of the carboxyl moiety is replaced by —OR⁴⁴.

“An inhibitor of L-aromatic amino acid decarboxylase” preferably refersto L-aromatic amino acid decarboxylase inhibitors such as carbidopa andbenzserazide optionally with a hydrogen atom of the amino or thehydrazido group of the L-aromatic amino acid decarboxylase inhibitorreplaced with —C(O)R¹⁰⁴, —C(O)OR¹⁰⁵ or an amino acid group, wherein R¹⁰⁴is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,aralkyl, substituted aralkyl, heteroaryl and substituted heteroaryl, andR¹⁰⁵ is selected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl,substituted aralkyl, heteroaryl and substituted heteroaryl; and/or

optionally with one or two hydrogen atoms of the two —OH groups of thecatechol or the three —OH groups of the pyrogallol group of theL-aromatic amino acid decarboxylase inhibitor are replaced with—C(O)R¹⁰⁴, —C(O)OR¹⁰⁵ and/or —OCR¹⁰³R¹⁰⁴OC(O)R¹⁰⁵ wherein R¹⁰⁵ isdefined as above, R¹⁰³ and R¹⁰⁴ independently are members selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, aralkyl, substitutedaralkyl, heteroaryl and substituted heteroaryl, or R¹⁰³ and R¹⁰⁴together with the carbon atom to which they are attached form acycloalkyl, substituted cycloalkyl, heterocycle or substitutedheterocyclic ring; or optionally with two adjacent —OH groups of thecatechol or pyrogallol group protected with a 5-membered cycliccarbonate or 2,3-dioxo-1,4-dioxane ortho fused with a benzene ring ofthe catechol or pyrogallol group; and/or

the OH group of the carboxyl moiety is replaced by —OR¹⁰⁴.

“Derivatives of L-DOPA” preferably refers to L-DOPA molecules wherein:

a) a hydrogen atom of the amino group of the L-DOPA molecule is replacedwith —C(O)R¹¹⁴, —C(O)OR¹¹⁵ or an amino acid group, wherein R¹¹⁴ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,aralkyl, substituted aralkyl, heteroaryl and substituted heteroaryl, andR¹¹⁵ is selected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl,substituted aralkyl, heteroaryl and substituted heteroaryl; and/or

b) one or two hydrogen atoms of the two —OH groups of the catechol groupof the L-DOPA molecule are replaced with —C(O)R¹¹⁴, —C(O)OR¹¹⁵ and/or—OCR¹¹³R¹¹⁴OC(O)R¹¹⁵ wherein R¹¹⁵ is defined as above, R¹¹³ and R¹¹⁴independently are members selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl andsubstituted heteroaryl, or R¹¹³ and R¹¹⁴ together with the carbon atomto which they are attached form a cycloalkyl, substituted cycloalkyl,heterocycle or substituted heterocyclic ring, or the two —OH groups ofthe catechol group of the L-DOPA molecule are protected with a5-membered cyclic carbonate or 2,3-dioxo-1,4-dioxane ortho fused with abenzene ring of the catechol group of the L-DOPA molecule; and/or

c) the OH group of the carboxyl moiety is replaced by —OR¹¹⁴.

“Acidic heterocycle” refers to a reprotonatable heterocycle having a pKaless than 7.0. Examples of such heterocycles include the following:

“Linear oligopeptide” refers to an amide oligomer comprising either aterminal amino group or a terminal carboxylic acid group or (preferably)both a terminal amino group and a terminal carboxylic acid group, whicholigomer is formed by condensation of the terminal amino residue of atleast one amino acid with the terminal carboxylic acid residue of atleast a second amino acid. The amino acids comprising the oligopeptideare either α-amino acids, β-amino acids, or a mixture of α-amino acidsand β-amino acids. Note that when an α-amino acid additionally containseither a β-amino group or a β-carboxylic acid group (e.g. as in asparticacid) a linear oligopeptide formed from such an amino acid is intendedto imply that it is the α-amine or α-carboxylic acid moiety (or both) ofsuch residue that is involved in amide formation.

“Derived from a compound” or “derivative” refers to a moiety that isstructurally related to such a compound. The structure of the moiety isidentical to the compound except at 1 or 2 positions. At these positionseither a hydrogen atom attached to a heteroatom, or a hydroxyl moiety ofa carboxylic, phosphonic, phosphoric or sulfonic acid group has beenreplaced with a covalent bond that serves as a point of attachment toanother moiety. For example, the moiety:

is derived from a linear oligopeptide comprising glycine and the druggabapentin. In this moiety, a hydrogen atom has been replaced with acovalent bond. “Derived from a linear oligopeptide” is meant tospecifically denote that the point of attachment is either the terminalamino group or the terminal acid group of the oligopeptide.

The term “systemic bioavailability” refers to the rate and extent ofsystemic exposure to a drug or a metabolite thereof as reflected by thearea under the systemic blood concentration versus time curve.

“Translocation across the intestinal wall” refers to movement of a drugor drug conjugate by a passive or active mechanism, or both, across anepithelial cell membrane of any region of the gastrointestinal tract.

“Active metabolite of a drug” refers to products of in vivo modificationof the drug which have therapeutic or prophylactic effect.

“Therapeutic or prophylactic blood concentrations” refers to systemicexposure to a sufficient concentration of a drug or an active metabolitethereof over a sufficient period of time to effect disease therapy or toprevent the onset or reduce the severity of a disease in the treatedanimal.

“Sustained release” refers to release of a drug or an active metabolitethereof into the systemic circulation over a prolonged period of timerelative to that achieved by oral administration of a conventionalformulation of the drug.

“Tissue of the enterohepatic circulation” refers to the blood, plasma,intestinal contents, intestinal cells, liver cells, biliary tract or anyfraction, suspension, homogenate, extract or preparation thereof.

“Conjugating” refers to the formation of a covalent bond.

“Bile acid transport system” refers to any membrane transporter proteincapable of causing a bile acid or a derivative thereof to betranslocated across a membrane of a cell of the gastrointestinal tractor liver.

“Active transport or active transport mechanism” refers to the movementof molecules across cellular membranes that: a) is directly orindirectly dependent on an energy mediated process (i.e. driven by ATPhydrolysis, ion gradient, etc); or b) occurs by facilitated diffusionmediated by interaction with specific transporter proteins; or c) occursthrough a modulated solute channel.

“A moiety selected to permit a compound of formula (I) to betranslocated across the intestinal wall of an animal via the bile acidtransport system” refers to compounds which, when conjugated to the drug(directly or via a linker moiety), are translocated across theintestinal wall via the bile acid transport system. Evaluation of whichcandidate compounds can be so translocated across the intestinal wallcan be conducted by the in vitro assay set forth in Example 3 below.

“Practical dosage regimen” refers to a schedule of drug administrationthat is practical for a patient to comply with. For human patients, apractical dosage regimen for an orally administered drug is likely to bean aggregate dose of less than 10 g/day.

“Amino-protecting group” or “amino-blocking group” refers to any groupwhich when bound to one or more amino groups prevents reactions fromoccurring at these amino groups and which protecting groups can beremoved by conventional chemical steps to reestablish the amino group.The particular removable blocking group is not critical and preferredamino blocking groups include, by way of example only, t-butyoxycarbonyl(t-BOC), benzyloxycarbonyl (CBZ), and the like.

“Carboxyl-protecting group” or “carboxyl-blocking group” refers to anygroup which when bound to one or more carboxyl groups prevents reactionsfrom occurring at these groups and which protecting groups can beremoved by conventional chemical steps to reestablish the carboxylgroup. The particular removable blocking group is not critical andpreferred carboxyl blocking groups include, by way of example only,esters of the formula —COOR″ where R″ is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,aryl, substituted aryl, alkaryl, substituted alkaryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic.

“Alkyl” refers to alkyl groups preferably having from 1 to 20 carbonatoms and more preferably 1 to 6 carbon atoms. This term is exemplifiedby groups such as methyl, t-butyl, n-heptyl, octyl, dodecyl and thelike.

“Substituted alkyl” refers to an alkyl group, preferably of from 1 to 20carbon atoms, having from 1 to 5 substituents selected from the groupconsisting of alkoxy, substituted alkoxy, acyl, acylamino,thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino,aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl,substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl,carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl,carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substitutedaryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic,cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substitutedheteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkyl/substituted alkyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkoxy” refers to the group “alkyl-O-” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” refers to the group “substituted alkyl-O—”. “Acyl”refers to the groups H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—,alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substitutedalkynyl-C(O)-cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, aryl-C(O)—,substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O),heterocyclic-C(O)—, and substituted heterocyclic-C(O)— wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein.

“Acylamino” refers to the group —C(O)NRR where each R is independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic and whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Thiocarbonylamino” refers to the group —C(S)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form, together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, heteroaryl-C(O)O—, substitutedheteroaryl-C(O)O—, heterocyclic-C(O)O—, and substitutedheterocyclic-C(O)O— wherein alkyl, substituted alkyl alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Alkenyl” refers to alkenyl group preferably having from 2 to 20 carbonatoms and more preferably 2 to 6 carbon atoms and having at least 1 andpreferably from 1-2 sites of alkenyl unsaturation.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkenyloxy” refers to the group —O-alkenyl.

“Substituted alkenyloxy” refers to the group —O-substituted alkenyloxy.

“Alkynyl” refers to alkynyl group preferably having from 2 to 20 carbonatoms and more preferably 3 to 6 carbon atoms and having at least 1 andpreferably from 1-2 sites of alkynyl unsaturation.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkylene” refers to a divalent alkylene group preferably having from 1to 20 carbon atoms and more preferably 1 to 6 carbon atoms. This term isexemplified by groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

“Substituted alkylene” refers to alkylene groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkenylene” refers to a divalent alkenylene group preferably havingfrom 2 to 20 carbon atoms and more preferably 1 to 6 carbon atoms andhaving from 1 to 2 sites of alkenyl unsaturation. This term isexemplified by groups such as ethenylene (—CH═CH—), propenylene(—CH₂CH═CH—), and the like.

“Substituted alkenylene” refers to alkenylene groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkynylene” refers to a divalent alkynylene group preferably havingfrom 2 to 20 carbon atoms and more preferably 1 to 6 carbon atoms andhaving from 1 to 2 sites of alkynyl unsaturation. This term isexemplified by groups such as ethynylene, propynylene and the like.

“Substituted alkynylene” refers to alkynylene groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Amidino” refers to the group H₂NC(═NH)— and the term “alkylamidino”refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC(═NH)—).

“Thioamidino” refers to the group RSC(═NH)— where R is hydrogen oralkyl.

“Aminoacyl” refers to the groups —NRC(O)alkyl, —NRC(O)substituted alkyl,—NRC(O)cycloalkyl, —NRC(O)substituted cycloalkyl, —NRC(O)alkenyl,—NRC(O)substituted alkenyl, —NRC(O)alkynyl, —NRC(O)substituted alkynyl,—NRC(O)aryl, —NRC(O)substituted aryl, —NRC(O)heteroaryl,—NRC(O)substituted heteroaryl, —NRC(O)heterocyclic, and—NRC(O)substituted heterocyclic where R is hydrogen or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminocarbonyloxy” refers to the groups —NRC(O)O-alkyl,—NRC(O)O-substituted alkyl, —NRC(O)O-alkenyl, —NRC(O)O-substitutedalkenyl, —NRC(O)O-alkynyl, —NRC(O)O-substituted alkynyl,—NRC(O)O-cycloalkyl, —NRC(O)O-substituted cycloalkyl, —NRC(O)O-aryl,—NRC(O)O-substituted aryl, —NRC(O)O-heteroaryl, —NRC(O)O-substitutedheteroaryl, —NRC(O)O-heterocyclic, and —NRC(O)O-substituted heterocyclicwhere R is hydrogen or alkyl and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxycarbonylamino” refers to the groups —OC(O)NH₂, —OC(O)NRR,—OC(O)NR-alkyl, —OC(O)NR-substituted alkyl, —OC(O)NR-alkenyl,—OC(O)NR-substituted alkenyl, —OC(O)NR-alkynyl, —OC(O)NR-substitutedalkynyl, —OC(O)NR-cycloalkyl, —OC(O)NR-substituted cycloalkyl,—OC(O)NR-aryl, —OC(O)NR-substituted aryl, —OC(O)NR-heteroaryl,—OC(O)NR-substituted heteroaryl, —OC(O)NR-heterocyclic, and—OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form, together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxythiocarbonylamino” refers to the groups —OC(S)NH₂, —OC(S)NRR,—OC(S)NR-alkyl, —OC(S)NR-substituted alkyl, —OC(S)NR-alkenyl,—OC(S)NR-substituted alkenyl, —OC(S)NR-alkynyl, —OC(S)NR-substitutedalkynyl, —OC(S)NR-cycloalkyl, —OC(S)NR-substituted cycloalkyl,—OC(S)NR-aryl, —OC(S)NR-substituted aryl, —OC(S)NR-heteroaryl,—OC(S)NR-substituted heteroaryl, —OC(S)NR-heterocyclic, and—OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminocarbonylamino” refers to the groups —NRC(O)NRR, —NRC(O)NR-alkyl,—NRC(O)NR-substituted alkyl, —NRC(O)NR-alkenyl, —NRC(O)NR-substitutedalkenyl, —NRC(O)NR-alkynyl, —NRC(O)NR-substituted alkynyl,—NRC(O)NR-aryl, —NRC(O)NR-substituted aryl, —NRC(O)NR-cycloalkyl,—NRC(O)NR-substituted cycloalkyl, —NRC(O)NR-heteroaryl, and—NRC(O)NR-substituted heteroaryl, —NRC(O)NR-heterocyclic, and—NRC(O)NR-substituted heterocyclic where each R is independentlyhydrogen, alkyl or where each R is joined to form together with thenitrogen atom a heterocyclic or substituted heterocyclic ring as well aswhere one of the amino groups is blocked by conventional blocking groupssuch as Boc, Cbz, formyl, and the like and wherein alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminothiocarbonylamino” refers to the groups —NRC(S)NRR,—NRC(S)NR-alkyl, —NRC(S)NR-substituted alkyl, —NRC(S)NR-alkenyl,—NRC(S)NR-substituted alkenyl, —NRC(S)NR-alkynyl, —NRC(S)NR-substitutedalkynyl, —NRC(S)NR-aryl, —NRC(S)NR-substituted aryl,—NRC(S)NR-cycloalkyl, —NRC(S)NR-substituted cycloalkyl,—NRC(S)NR-heteroaryl, and —NRC(S)NR-substituted heteroaryl,—NRC(S)NR-heterocyclic, and —NRC(S)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aryl” or “Ar” refers to a monovalent unsaturated aromatic carbocyclicgroup of from 6 to 14 carbon atoms having a single ring (e.g., phenyl)or multiple condensed rings (e.g., naphthyl or anthryl) which condensedrings may or may not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7yl, and the like). Preferred aryls includephenyl and naphthyl. Substituted aryl refers to aryl groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Arylene” refers to a divalent unsaturated aromatic carbocyclic group offrom 6 to 14 carbon atoms having a single ring (e.g., phenylene) ormultiple condensed rings (e.g., naphthylene or anthrylene) whichcondensed rings may or may not be aromatic. Preferred arylenes includephenylene and naphthylene. Substituted arylene refers to arylene groupswhich are substituted with from 1 to 3 substituents selected from thegroup consisting of hydroxy, acyl, acylamino, thiocarbonylamino,acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR—substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Aryloxy” refers to the group aryl-O— which includes, by way of example,phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to substituted aryl-O— groups.

“Aryloxyaryl” refers to the group -aryl-O-aryl.

“Substituted aryloxyaryl” refers to aryloxyaryl groups substituted withfrom 1 to 3 substituents on either or both aryl rings selected from thegroup consisting of hydroxy, acyl, acyl amino, thiocarbonyl amino,acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 8 carbon atomshaving a single cyclic ring including, by way of example, cyclopropyl,cyclobutyl, cyclopentyl, cyclooctyl and the like. Excluded from thisdefinition are multi-ring alkyl groups such as adamantanyl, etc.

“Cycloalkyloxy” refers to —O-cycloalkyl.

“Cycloalkenyl” refers to cyclic alkenyl groups of frm 3 to 8 carbonatoms having a single cyclic ring.

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Substituted cycloalkyl” and “substituted cycloalkenyl” refers to ancycloalkyl or cycloalkenyl group, preferably of from 3 to 8 carbonatoms, having from 1 to 5 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkynyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkynyl/substituted alkynyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Substituted cycloalkyloxy” and “substituted cycloalkenyloxy” refers to—O-substituted cycloalkyl and —O-substituted cycloalkenyloxyrespectively.

“Cycloalkylene” refers to divalent cyclic alkylene groups of from 3 to 8carbon atoms having a single cyclic ring including, by way of example,cyclopropylene, cyclobutylene, cyclopentylene, cyclooctylene and thelike.

“Cycloalkenylene” refers to a divalent cyclic alkenylene groups of frm 3to 8 carbon atoms having a single cyclic ring.

“Substituted cycloalkylene” and “substituted cycloalkenylene” refers toa cycloalkylene or cycloalkenylene group, preferably of from 3 to 8carbon atoms, having from 1 to 5 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkynyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkynyl/substituted alkynyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Cycloalkoxy” refers to —O-cycloalkyl groups.

“Substituted cycloalkoxy” refers to —O-substituted cycloalkyl groups.

“Guanidino” refers to the groups —NRC(═NR)NRR, —NRC(═NR)NR-alkyl,—NRC(═NR)NR-substituted alkyl, —NRC(═NR)NR-alkenyl,—NRC(═NR)NR-substituted alkenyl, —NRC(═NR)NR-alkynyl,—NRC(═NR)NR-substituted alkynyl, —NRC(═NR)NR-aryl,—NRC(═NR)NR-substituted aryl, —NRC(═NR)NR-cycloalkyl,—NRC(═NR)NR-heteroaryl, —NRC(═NR)NR-substituted heteroaryl,—NRC(═NR)NR-heterocyclic, and —NRC(═NR)NR-substituted heterocyclic whereeach R is independently hydrogen and alkyl as well as where one of theamino groups is blocked by conventional blocking groups such as Boc,Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“N,N-Dimethylcarbamyloxy” refers to the group —OC(O)N(CH₃)₂.

“Guanidinosulfone” refers to the groups —NRC(═NR)NRSO₂-alkyl,—NRC(═NR)NRSO₂-substituted alkyl, —NRC(═NR)NRSO₂-alkenyl,—NRC(═NR)NRSO₂-substituted alkenyl, —NRC(═NR)NRSO₂-alkynyl,—NRC(═NR)NRSO₂-substituted alkynyl, —NRC(═NR)NRSO₂-aryl,—NRC(═NR)NRSO₂-substituted aryl, —NRC(═NR)NRSO₂-cycloalkyl,—NRC(═NR)NRSO₂-substituted cycloalkyl, —NRC(═NR)NRSO₂-heteroaryl, and—NRC(═NR)NRSO₂-substituted heteroaryl, —NRC(═NR)NRSO₂-heterocyclic, and—NRC(═NR)NRSO₂-substituted heterocyclic where each R is independentlyhydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either chloro or bromo.

“Heteroaryl” refers to an aromatic carbocyclic group of from 2 to 10carbon atoms and 1 to 4 heteroatoms selected from the group consistingof oxygen, nitrogen and sulfur within the ring. Such heteroaryl groupscan have a single ring (e.g., pyridyl or furyl) or multiple condensedrings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls includepyridyl, pyrrolyl, indolyl and furyl.

“Substituted heteroaryl” refers to heteroaryl groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Heteroarylene” refers to a divalent aromatic carbocyclic group of from2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the groupconsisting of oxygen, nitrogen and sulfur within the ring. Suchheteroarylene groups can have a single ring (e.g., pyridylene orfurylene) or multiple condensed rings (e.g., indolizinylene orbenzothienylene). Preferred heteroarylenes include pyridylene,pyrrolylene, indolylene and furylene.

“Substituted heteroarylene” refers to heteroarylene groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Heteroaryloxy” refers to the group —O-heteroaryl and “substitutedheteroaryloxy” refers to the group —O-substituted heteroaryl.

“Heterocycle” or “heterocyclic” refers to a saturated or unsaturatedgroup having a single ring or multiple condensed rings, from 1 to 10carbon atoms and from 1 to 4 hetero atoms selected from the groupconsisting of nitrogen, sulfur or oxygen within the ring wherein, infused ring systems, one or more the rings can be aryl or heteroaryl.

“Substituted heterocyclic” refers to heterocycle groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and thelike.

“Heterocyclene” refers to a divalent saturated or unsaturated grouphaving a single ring or multiple condensed rings, from 1 to 10 carbonatoms and from 1 to 4 hetero atoms selected from the group consisting ofnitrogen, sulfur or oxygen within the ring wherein, in fused ringsystems, one or more the rings can be aryl or heteroaryl.

“Substituted heterocyclene” refers to heterocyclene groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Heterocyclyloxy” refers to the group —O-heterocyclic and “substitutedheterocyclyloxy” refers to the group —O-substituted heterocyclic.

“Thiol” refers to the group —SH.

“Thioalkyl” refers to the groups —S-alkyl

“Substituted thioalkyl” refers to the group —S-substituted alkyl.

“Thiocycloalkyl” refers to the groups —S-cycloalkyl.

“Substituted thiocycloalkyl” refers to the group —S-substitutedcycloalkyl.

“Thioaryl” refers to the group —S-aryl and “substituted thioaryl” refersto the group —S-substituted aryl.

“Thioheteroaryl” refers to the group —S-heteroaryl and “substitutedthioheteroaryl” refers to the group —S-substituted heteroaryl.

“Thioheterocyclic” refers to the group —S-heterocyclic and “substitutedthioheterocyclic” refers to the group —S-substituted heterocyclic.

“Amino” refers to the —NH₂ group.

“Substituted amino” refers to the —NR′R″ group wherein R′ and R″ areindependently hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic or where R′ and R″,together with the nitrogen atom pendent thereto, form a heterocyclicring.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound of Formulae (I), which salts are derived from avariety of organic and inorganic counter ions well known in the art andinclude, by way of example only, sodium, potassium, calcium, magnesium,ammonium, tetraalkylammonium, and the like; and when the moleculecontains a basic functionality, salts of organic or inorganic acids,such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate and the like.

Utility

The compounds and methods described herein provide for the sustainedrelease of drugs or active metabolites thereof relative to dosing withthe parent drug itself. In this regard, enterohepatic recycling of thebile acid conjugates creates a reservoir for the active agent.

General Synthetic Scheme

Compounds of this invention can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

These schemes are merely illustrative of some methods by which thecompounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to oneskilled in the art having referred to this disclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Preparation of Compounds of Formula (I)

Schemes A and B describe alternative methods to prepare the compounds ofFormula (I).

Compounds of formula (I-1) where X, R¹ and R² are hydroxy, Z is asubstituted alkyl group containing a group of the formula -M-Q^(x′), Mis —CH₂CH₂C(O)—, Q^(x′) is of the structure -A^(x′)-D′, A^(x′) isderived from an α-amino acid, and D′ is a drug of formula (b):

can be prepared as illustrated and described in Scheme A below.

In reference to Scheme A, commercially available cholic acid (A) istreated with an activating agent, such as ethylchloroformate in thepresence of diisopropylethylamine, to provide an activated anhydride.The activated anhydride is reacted with amino acid (a) forming acid (B).Activation of (B) using an activating agent and condensation with drug(b) affords a compound of formula (I-1) as shown.

One of ordinary skill in the art will appreciate that cholic acid (A)could alternatively be reacted with amino acid (a) in the presence of acoupling agent (e.g., dicyclohexylcarbodiimide) to provide acid (B).Alternatively, cholic acid (A) could be coupled with the dipeptide (ordepsipeptide) resulting from first coupling amino acid (a) to compound(b).

A compound of formula (I-2) where R¹ and R² are hydroxy, Z is—CH₂CH₂CO₂H, X is Q^(x)-G-, G is —O—, Q^(x) is -D-A^(x), A^(x) isderived from an α-amino acid, and D is a drug of formula (b):

can be prepared as illustrated and described in Scheme B below.

In reference to Scheme B, compound (C), wherein R¹⁰⁰ is a carboxylprotecting group, is coupled with activated acid derivative (c), whereinR¹⁰¹ is a suitable leaving group (e.g., —OC(O)OEt). Selectivedeprotection of the amino or hydroxyl protecting group (i.e., Pg)provides compound (D). Activation of carboxylic acid (d) (e.g.,treatment with ethyl chloroformate in the presence of a tertiary amine)followed by addition to (D) then removal of protecting groups yields thedesired compound of formula (I-2).

One of ordinary skill in the art will appreciate that one could also usea coupling agent (e.g. a carbodiimide) in situ to form the amide orester bonds above (i.e., bond between (C) and (c) or between (D) and(d)) rather than condensing a preformed activated acid derivative (i.e.,(c) or (d)).

Analogous synthetic methods can be used in the preparation of compoundsof formula (II) and (III).

Additionally, FIGS. 4-8 and Examples 1-8 below describe in detail thesynthesis and biological activity of various bile acid-derivedcompounds.

Pharmaceutical Formulations

When employed as pharmaceuticals, the compounds of formula (I), (II) or(III) are usually administered in the form of pharmaceuticalcompositions. These compounds can be administered by a variety of routesincluding oral, rectal, subcutaneous, intravenous, intramuscular andintranasal. These compounds are effective as both injectable and oralcompositions. Such compositions are prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of formula (I)above associated with pharmaceutically acceptable carriers. In makingthe compositions of this invention, the active ingredient is usuallymixed with an excipient, diluted by an excipient or enclosed within sucha carrier which can be in the form of a capsule, sachet, paper or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.1 to about 5000 mg, more usually about 10to about 2000 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 mg to about 2 g of the activeingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solventsor mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be breathed directly from thenebulizing device or the nebulizing device may be attached to a facemasks tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

Atm=atmosphere

Boc=tert-butyloxycarbonyl

Cbz=carbobenzyloxy

CPM=counts per minute

DIC=diisopropylcarbodiimide

DMAP=4-N,N-dimethylaminopyridine

DMEM=Dulbecco's minimun eagle medium

DMF=N,N-dimethylformamide

DMSO=dimethylsulfoxide

FMOC=9-fluorenylmethyloxycarbonyl

g=gram

h=hour

HBSS=Hank's buffered saline solution

IBAT=intestinal bile acid transporter

L=liter

LBAT=liver bile acid transporter

LC/MS=liquid chromatography/mass spectroscopy

M=molar

min=minute

mL=milliliter

mmol=millimols

NTCP=Na+ taurocholate cotransporting polypeptide

PBS=phosphate buffered saline

PPTS=pyridinium p-toluenesulfonate

THF=tetrahydrofuran

TFA=trifluoroacetic acid

TMSOTf=trimethylsilyltrifluoromethanesulfonate

Trisyl=2,4,6-triispropylbenzenesulfonyl

μL=microliter

μM=micromolar

v/v volume to volume

Experimental Methods

The following examples illustrate how the synthesis of GABA analogconjugates could be conducted in order to prepare compounds of formula(I). It is contemplated that other drugs may be used in place of a GABAanalog with similar synthetic schemes. The syntheses described below areillustrated in FIG. 4-8. While GABA is not included within the scope ofthis invention, these examples are illustrative of how other drugs couldbe readily coupled to a bile acid in an analogous manner.

Example 1 Synthesis of Cholic Acid Gabapentin Dipeptides (9)

Cholic acid (6) (408 mg, 1 mmol) was dissolved in anhydrous THF (10 mL)and triethylamine (0.167 mL, 1.2 mmol) added slowly with stirring. Thesolution was cooled to −5° C. in an ice-salt bath, and ethylchloroformate (0.12 mL, 1.2 mmol) added slowly, maintaining thetemperature between —5 to 0° C. After addition was complete, the coldmixture was stirred for an additional 15 minutes. A solution containingan amino acid (7) (1.75 mmol) in 2N NaOH (2 mL) was added and themixture stirred for an additional 60 min at −5 to 0° C. After removal ofthe THF in vacuo, saturated NaHCO₃ (15 mL) was added and the aqueousmixture washed with EtOAc (3×10 mL), then the pH adjusted to 3-4 withcitric acid. The product was extracted into EtOAc (3×15 mL), and thecombined organic phase dried over MgSO₄, and concentrated to dryness.The residue was purified by flash chromatography on silica gel (5%MeOH/CH₂Cl₂) to give the pure cholic acid adduct (8). This compound (0.4mmol) was dissolved in anhydrous THF (10 mL) and triethylamine (0.44mmol) added slowly with stirring. The solution was cooled to −5° C. inan ice-salt bath, and ethyl chloroformate (44 μL, 0.44 mmol) addedslowly, maintaining the temperature between −5 to 0° C. After additionwas complete, the cold mixture was stirred for an additional 15 minutes.A solution containing gabapentin (2) (166 mg, 0.8 mmol) in 2N NaOH (3mL) was added and the mixture stirred for an additional 60 min at −5 to0°C. After removal of the THF in vacuo, saturated NaHCO₃ (10 mL) wasadded and the aqueous mixture washed with EtOAc (3×10 mL), then the pHadjusted to 3-4 with citric acid. The product was extracted into EtOAc(3×20 mL), and the combined organic phases dried over MgSO₄, andconcentrated to dryness. The residue was purified by flashchromatography on silica gel (10% MeOH/CH₂Cl₂) to give the pure cholicacid gabapentin dipeptide derivative. The corresponding sodium salt (9)was prepared in quantitative yield by addition of a methanol solution ofthe acid to water containing 0.5N NaOH (1 eq.) and evaporation todryness on a lyophilizer. Compounds were characterized by electrospraymass spectrometry as reported below:

Cholyl-Gly-Gabapentin (9a): MS (ESI): m/z 617.50 (M−H⁻), 619.51 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.81 (s, 2H),3.34 (s, 2H), 2.28 (s, 2H), 1.03 (d, 3H, J=6.4Hz), 0.91 (s, 3H), 0.70(s, 3H).

Cholyl-Ala-Gabapentin (9b): MS (ESI): m/z 631.50 (M−H⁻), 633.52 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.29 (m, 1H),3.34 (s, 2H), 2.28 (s, 2H), 1.34 (d, 2H, J=6.8 Hz), 1.01 (d, 3H, J=6.4Hz), 0.91 (s, 3H), 0.71 (s, 3H).

Cholyl-Val-Gabapentin (9c): MS (ESI): m/z 659.55 (M−H⁻), 661.55 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.26 (m, 1H),3.34 (s, 2H), 2.27 (s, 2H), 1.02 (d, 3H, J=6.4 Hz), 0.97 (d, 6H, J=6.4Hz), 0.91 (s, 3H), 0.71 (s, 3H).

Cholyl-Leu-Gabapentin (9d): MS (ESI): m/z 673.43 (M−H⁻), 675.45 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.34 (m, 1H),3.34 (s, 2H), 2.27 (s, 2H), 1.02 (d, 3H, J=6.4 Hz), 0.97 (d, 3H, J=6.4Hz), 0.92 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.70 (s, 3H).

Cholyl-Norleu-Gabapentin (9e): MS (ESI): m/z 659.56 (M−H⁻), 661.57(M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.26 (m, 1H),3.34 (s, 2H), 2.27 (s, 2H), 1.02 (d, 3H, J=6.4Hz), 0.91 (s, 3H), 0.71(s, 3H).

Cholyl-BuGly-Gabapentin (9f): MS (ESI): m/z 673.58 (M−H⁻), 675.58(M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.20 (s, 1H),3.34 (s, 2H), 2.29 (s, 2H), 1.01 (d, 3H, J=6.4Hz), 0.98 (s, 9H), 0.91(s, 3H), 0.70 (s,3H).

Cholyl-Phe-Gabapentin (9g): MS (ESI): m/z 707.47 (M−H⁻), 709.36 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.26 (m, 5H),4.59 (m, 1H), 3.34 (s, 2H), 3.25-2.95 (m, 2H), 2.18 (d, 2H, J=7.2 Hz),0.98 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.68 (s, 3H).

Cholyl-Tyr-Gabapentin (9h): MS (ESI): m/z 723.42 (M−H⁻), 725.42 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.06 (d, 2H,J=8.8 Hz), 6.69 (d, 2H, J=8.8 Hz), 4.51 (dd,1H, J=6.8 Hz, J=8.8 Hz),3.34 (s, 2H), 3.16-2.78 (m, 2H), 2.16 (d, 2H, J=7.2 Hz), 0.98 (d, 3H,J=6.4 Hz), 091 (s, 3H), 0.68 (s, 3H).

Cholyl-Ser-Gabapentin (9i): MS (ESI): m/z 647.42 (M−H⁻), 649.41 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.37 (m, 1H),3.78 (m, 2H), 3.34 (s, 2H), 2.15 (s, 2H), 1.03 (d, 3H, J=6.4Hz), 0.91(s, 3H), 0.71 (s, 3H).

Cholyl-Asp-Gabapentin (9j): MS (ESI): m/z 647.45 (M−H⁻), 649.45 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.71 (m, 1H),3.34 (s, 2H), 2.87-2.65 (m, 2H), 2.28 (s, 2H), 1.02 (d, 3H, J=6.4 Hz),0.91 (s, 3H), 0.71 (s, 3H).

Cholyl-Glu-Gabapentin (9k): MS (ESI): m/z 688.50 (M−H⁻), 690.54 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.35 (m, 1H),3.34 (s, 2H), 2.38 (t, 2H, J=7 Hz), 1.02 (d, 3H, J=6.4 Hz), 0.91 (s,3H), 0.71 (s, 3H).

Cholyl-Asn-Gabapentin (9I): MS (ESI): m/z 674.43 (M−H⁻), 676.44 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.29 (m, 1H),3.34 (s, 2H), 2.92-2.69 (m, 2H), 2.28 (s, 2H), 1.02 (d, 3H, J=6.4 Hz),0.91 (s, 3H), 0.70 (s, 3H).

Cholyl-Lys-Gabapentin (9m): MS (ESI): m/z 688.50 (M−H⁻), 690.54 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.29 (m, 1H),3.34 (s, 2H), 2.28 (s, 2H), 1.02 (d, 3H, J=6.4Hz), 0.91 (s, 3H), 0.70(s, 3H).

Cholyl-β-Ala-Gabapentin (9n): MS (ESI): m/z 631.45 (M−H⁻), 633.45(M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.34 (s, 2H),3.20 (t, 2H, J=8 Hz), 2.29 (s, 2H), 2.26 (t, 2H, J=8 Hz), 1.02 (d, 3H,J=6.4 Hz), 0.91 (s, 3H), 0.70 (s, 3H).

Cholyl-Gaba-Gabapentin (9o): MS (ESI): m/z 645.56 (M−H⁻), 647.57 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.34 (s, 2H),3.41 (t, 2H, J=6.8 Hz), 2.44 (t, 2H, J=6.8 Hz), 2.28 (s, 2H), 1.01 (d,3H, J=6.4 Hz), 0.91 (s, 3H), 0.71 (s, 3H).

Ursodeoxycholyl-Phe-Gabapentin (9p): MS (ESI) m/z 691.6 (M−H⁻), 693.5(M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.26 (m, 5H),4.60 (m,1H), 3.34 (s, 2H), 3.25-2.95 (m, 2H), 2.08 (d, 2H, J=7 Hz), 0.95(s, 3H), 0.91 (d, 3H, J=6.4 Hz), 0.67 (s, 3H).

Alternative Synthesis of Cholic Acid Gabapentin Dipeptides (9)

An N-Fmoc-protected amino acid (10) (1 mmol) is dissolved in anhydrousTHF (10 mL) and triethylamine (0.167 mL, 1.2 mmol) added slowly withstirring. The solution is cooled to −5° C. in an ice-salt bath, andethyl chloroformate (0.12 mL, 1.2 mmol) added slowly, maintaining thetemperature between −5 to 0° C. After addition is complete, the coldmixture is stirred for an additional 15 minutes. A solution containinggabapentin (2) (1.75 mmol) in 2N NaOH (2 mL) is added and the mixturestirred for an additional 60 min at −5 to 0° C. After removal of the THFin vacuo, saturated NaHCO₃ (15 mL) is added and the aqueous mixturewashed with EtOAc (3×10 mL), then the pH adjusted to 3-4 with citricacid. The product is extracted into EtOAc (3×15 mL), and the combinedorganic phase dried over MgSO₄, and concentrated to dryness. The residueis purified by flash chromatography on silica gel (5% MeOH/CH₂Cl₂) togive the pure protected dipeptide adduct. This compound is dissolved indry NMP (4 mL) containing 5% (v/v) DBU and the solution stirred for 30min to give the dipeptide (11). Cholic acid (6) (1 mmol) is dissolved inanhydrous THF (10 mL) and triethylamine (0.167 mL, 1.2 mmol) addedslowly with stirring. The solution is cooled to −5° C. in an ice-saltbath, and ethyl chloroformate (0.12 mL, 1.2 mmol) added slowly,maintaining the temperature between −5 to 0° C. After addition iscomplete, the cold mixture is stirred for an additional 15 minutes. Theabove solution of dipeptide (11) is added and the mixture stirred for anadditional 60 min at −5 to 0° C. After removal of the solvent in vacuo,saturated NaHCO₃ (15 mL) is added and the aqueous mixture washed withEtOAc (3×10 mL), then the pH adjusted to 3-4 with citric acid. Theproduct is extracted into EtOAc (3×15 mL), and the combined organicphase dried over MgSO₄, and concentrated to dryness. The residue ispurified by flash chromatography on silica gel (10% MeOH/CH₂Cl₂) to givethe pure cholic acid gabapentin dipeptide derivative. The correspondingsodium salt (9) is prepared in quantitative yield by addition of amethanol solution of the acid to water containing 0.5N NaOH (1 eq.) andevaporation to dryness on a lyophilizer.

Example 2 Synthesis of Cholic Acid Pregabalin Dipeptides (12)

Pregabalin (3), prepared according the methods described in Silverman etal (U.S. Pat. No. 5,563,175), is transformed to the cholyl dipeptidederivative (12) following the procedure detailed above for thegabapentin analog (9).

Example 3 In Vitro Compound Transport Assays with IBAT andLBAT-Expressing Cell Lines

(a) Inhibition of Radiolabeled Taurocholate Uptake

CHO cells transfected with the IBAT or LBAT transporter were seeded into96-well microtiter plates at 100,000 cells/well in 100 μL DMEMcontaining 10% serum, glutamine and Penstrep. After overnight incubationthe media was removed and test compound (25 μL) added at 2× the finaldesired concentration. Tritiated taurocholate (50,000 CPM/well) wasdiluted with cold substrate to a final concentration of 5 μM and 25μL/well of this mixture was added to the plate. After incubating for 1 hat room temperature the solution was removed and the plate washed 4×with PBS at 4° C. 200 μL/well of scintillant is added and the plate thenread in a Wallac microbeta counter. The inhibition data is processed bystandard methods to calculate an inhibition constant K_(i) for the testcompound.

(b) Analysis of Electrogenic Transport in Xenopus Oocytes

RNA preparation: Human IBAT Transporter cDNAs were subcloned into amodified pGEM plasmid that contains 5′ and 3′ untranslated sequencesfrom the Xenopus μ-actin gene. These sequences increase RNA stabilityand protein expression. Plasmid cDNA was linearized and used as templatefor in vitro transcription (Epicentre Technologies transcription kit,4:1 methylated:non-methylated GTP).

Xenopus oocyte isolation. Xenopus laevis frogs were anesthetized byimmersion in Tricaine (1.5 g/mL in deionized water) for 15 min. Oocyteswere removed and digested in frog ringer solution (90 mM NaCl, 2 mM KCl,1 mM MgCl₂, 10 mM NaHEPES, pH 7.45, no CaCl₂) with 1 mg/mL collagenase(Worthington Type 3) for 80-100 min with shaking. The oocytes werewashed 6 times, and the buffer changed to frog ringer solutioncontaining CaCl₂ (1.8 mM). Remaining follicle cells were removed ifnecessary. Cells were incubated at 16° C., and each oocyte injected with10-20 μg RNA in 45 μL solution.

Electrophysiology measurements. Transport currents were measured 2-14days after injection, using a standard two-electrode electrophysiologyset-up (Geneclamp 500 amplifier, Digidata 1320/PCLAMP software andADInstruments hardware and software were used for signal acquisition).Electrodes (2-4 mΩ) were microfabricated using a Sutter Instrumentpuller and filled with 3M KCl. The bath was directly grounded(transporter currents were less than 0.3 μA). Bath flow was controlledby an automated perfusion system (ALA Scientific Instruments, solenoidvalves).

For transporter pharmacology, oocytes were clamped at −60 to −90 mV, andcontinuous current measurements acquired using PowerLab Software and anADInstruments digitizer. Current signals were lowpass filtered at 20 Hzand acquired at 4-8 Hz. All bath and drug-containing solutions were frogringers solution containing CaCl₂. Drugs were applied for 10-30 secondsuntil the induced current reached a new steady-state level, followed bya control solution until baseline currents returned to levels thatpreceded drug application. The difference current (baseline subtractedfrom peak current during drug application) reflected the net movement ofcharge resulting from electrogenic transport and was directlyproportional to tranport rate. Recordings were made from a single oocytefor up to 60 min, enabling 30-40 separate compounds to be tested peroocyte. Compound-induced currents were saturable and gave half-maximalvalues at substrate concentrations comparable to radiolabel competitionexperiments. To compare results between oocytes expressing differentlevels of transport activity, a saturating concentration ofglycodeoxycholate (300 μM) was used as a common reference to normalizeresults from test compounds. Using this normalization procedure V_(max)(i.e. maximal induced current) for different compounds tested ondifferent oocytes could be compared. TABLE 1 In vitro transport data forselected compounds on IBAT-expressing cells IC₅₀ COMPOUND (μM) EC₅₀ (μM)% Max. (GDC) Cholyl-Gly-Gabapentin (9a) 66 22 67 Cholyl-Phe-Gabapentin(9g) 92 140 28 Cholyl-Tyr-Gabapentin (9h) 52 160 13 UDC-Phe-Gabapentin(9p) 27 18 27IC₅₀ data from radiolabeled competition assay in transporter-expressingCHO cellsEC₅₀ and % Max data (relative to glycodeoxycholate) fromtransporter-expressing oocytes

TABLE 2 In vitro transport data for selected compounds onLBAT-expressing cells IC₅₀ COMPOUND (μM) EC₅₀ (μM) % Max. (GDC)Cholyl-Gly-Gabapentin (9a) 64 ND ND Cholyl-Phe-Gabapentin (9g) 0.5 ND NDCholyl-Tyr-Gabapentin (9h) 15 ND ND UDC-Phe-Gabapentin (9p) 0.7 ND NDIC₅₀ data from radiolabeled competition assay in transporter-expressingCHO cellsEC₅₀ and % Max data (relative to glycodeoxycholate) fromtransporter-expressing oocytes

Example 4 In Vitro Compound Transport Assays with PEPT1 andPEPT2-Expressing Cell Lines—Inhibition of Radiolabeled Gly-Sar Uptake

Rat and human PEPT1 and PEPT2 expressing CHO cell lines were prepared asdescribed in PCT Application WO01/20331. Gabapentin-containingdipeptides were evaluated for interaction with the peptide transportersusing a radiolabeled substrate uptake assay in a competitive inhibitionformat, as described in PCT Application WO01/20331. Transport-inducedcurrents were also measured in Xenopus oocytes transfected with rat andhuman PEPT1 and PEPT2. TABLE 3 In vitro transport data for selectedcompounds on rPEPT1-expressing cells IC₅₀ COMPOUND (μM) % Max. (Gly-Sar)Gly-Gabapentin 320 76 Phe-Gabapentin 56 52 Tyr-Gabapentin 130 22IC₅₀ data from radiolabeled competition assay in transporter-expressingCHO cells% Max response (relative to Gly-Sar) from transporter-expressing oocytesat a test compound concentration of 1 mM

TABLE 4 In vitro transport data for selected compounds onrPEPT2-expressing cells IC₅₀ COMPOUND (μM) % Max. (Gly-Sar)Gly-Gabapentin ND ND Phe-Gabapentin ND 77 Tyr-Gabapentin 4 73IC₅₀ data from radiolabeled competition assay in transporter-expressingCHO cells% Max response (relative to Gly-Sar) from transporter-expressing oocytesat a test compound concentration of 1 mM

Example 5 In Vitro Enzymatic Release of Gabapentin from Cholyl-AminoAcid-Gabapentin Conjugates

Sustained oral delivery of a drug molecule by attachment through acleavable linker arm to an actively transported promoiety requires thatthe drug eventually be released from the drug/cleavablelinker/transporter compound (prodrug) by enzymatic cleavage in one ormore tissues of the enterohepatic circulation. The release of Gabapentinfrom the prodrug Cholyl-Phe-Gabapentin (9g) (and other Cholyl-AminoAcid-Gabapentin conjugates (9)) was evaluated in vitro using tissuesrepresentative of those involved in the enterohepatic circulation. Thesestudies indicated that in vitro cleavage of the prodrug could occur viaa stepwise process, with release of the Gabapentin-containing dipeptide(e.g. Phe-Gabapentin) preceeding hydrolysis to liberate free Gabapentin.

Tissues were obtained from commercial sources (e.g., Pel-FreezBiologicals, Rogers, Ariz., or GenTest Corporation, Woburn, Mass.).Stability of Cholyl-Phe-Gabapentin towards specific enzymes (e.g.,carboxypeptidase A, cholylglycine hydrolase) was also evaluated byincubation with the purified enzyme.

Experimental conditions used for the in vitro studies are described inTable 3 below. Each preparation was incubated with (9g) at 37° C. forone hour. Aliquots (50 μL) were removed at 0, 30, and 60 min andquenched with 0.1% trifluoroacetic acid in acetonitrile. Samples werethen centrifuged and analyzed by LC/MS/MS as described below.

The stability of Gabapentin-containing dipeptides to purifiedaminopeptidase 1 and to Caco-2 homogenates was evaluated as follows:Aminopeptidase Stability: Aminopeptidase 1 (Sigma catalog # A-9934) wasdiluted in deionised water to a concentration of 856 units/mL. Stabilitystudies were conducted by incubating prodrug (5 μM) with 0.856 units/mLaminopeptidase 1 in 50 mM Tris-HCl buffer at pH 8.0 and 37° C.Concentrations of intact prodrug and released drug were determined atzero time and 60 minutes using LC/MS/MS.

Pancreatin Stability: Stability studies were conducted by incubatingprodrug (5 μM) with 1% (w/v) pancreatin (Sigma, P-1625, from porcinepancreas) in 0.025 M Tris buffer containing 0.5 M NaCl (pH 7.5) at 37°C. for 60 min. The reaction was stopped by addition of 2 volumes ofmethanol. After centrifugation at 14,000 rpm for 10 min, the supernatantwas removed and analyzed by LC/MS/MS.

Caco-2 Homogenate S9 Stability: Caco-2 cells were grown for 21 daysprior to harvesting. Culture medium was removed and cell monolayers wererinsed and scraped off into ice-cold 10 mM sodium phosphate0.15 Mpotassium chloride, pH 7.4. Cells were lysed by sonication at 4° C.using a probe sonicator. Lysed cells were then transferred into 1.5 mLcentrifuge vials and centrifuged at 9000 g for 20 min at 4° C. Theresulting supernatant (Caco-2 cell homogenate S9 fraction) was aliquotedinto 0.5 mL vials and stored at −80° C. until used. For stabilitystudies, prodrug (5 μM) was incubated in Caco-2 homogenate S9 fraction(0.5 mg protein per mL) for 60 min at 37° C. Concentrations of intactprodrug and released drug were determined at zero time and 60 minutesusing LC/MS/MS.

Concentrations of Cholyl-Phe-Gabapentin (9g), Phe-Gabapentin orGabapentin in tissue extracts were determined by direct injection ontoan API 2000 LC/MS/MS equipped with an Agilent 1100 binary pump andautosampler. Separation was achieved using a 3.5 μm Zorbax EllipseXDB-C8 4.4×150 mm column heated to 45° C. during the analysis. Themobile phases were: 0.1% formic acid in water (A) and 0.1% formic acidin acetonitrile (B). The gradient condition was: 2% B for 0.5 min,increasing to 90% B in 2.0 min, maintained for 2.5 min and returning to2% B for 2 min. A TurboIonSpray source was used on the API 2000. Theanalysis was performed in the positive ion mode and MRM transitions of709.5/172.1 and 172.0/137.2 were used in the analysis ofCholyl-Phe-Gabapentin (9g) and Gabapentin (2) respectively. Tenmicroliters of the sample extracts were injected. Peaks were integratedusing Analyst quantitation software. The method was linear for (9g) or(2) over the concentration range 0.01 to 12.5 μg/mL and 0.002 to 2.5μg/mL respectively. TABLE 5 In Vitro Enzymatic Release of Phe-Gabapentinfrom Cholyl-Phe- Gabapentin (9g) Percent of Phe- Substrate GabapentinPreparation Concentration Cofactors Released in 60 min Rat Plasma 2.0 μMNone NR Human Plasma 2.0 μM None NR Rat Liver S9 2.0 μM NADPH NR (0.5mg/mL) Human Liver S9 2.0 μM NADPH NR (0.5 mg/mL) Human Intestine 2.0 μMNADPH NR S9 (0.5 mg/mL) Cholylglycine 0.8 μM None ˜3 Hydrolase (87units/mL) Carboxypeptidase A 2.0 μM None NR (10 units/mL)NR = Not released

TABLE 6 In Vitro Enzymatic Release of Gabapentin (2) from Phe-GabapentinPercent of Substrate Gabapentin Preparation Concentration CofactorsReleased in 60 min Rat Plasma 2.0 μM None 19 Human Plasma 2.0 μM None NRRat Liver S9 2.0 μM NADPH  1 (0.5 mg/mL) Human Liver S9 2.0 μM NADPH  1(0.5 mg/mL) Human Intestine 2.0 μM NADPH  5 S9 (0.5 mg/mL) Cholylglycine0.8 μM None NR Hydrolase (87 units/mL) Carboxypeptidase A 2.0 μM None NR(10 units/mL) Caco-2 5.0 μM None 21 Homogenate Aminopeptidase 5.0 μMNone 24NR = Not released

TABLE 7 In Vitro Enzymatic Release of Gabapentin (2) from Cholyl-AminoAcid-Gabapentin Compounds by Pancreatin COMPOUND % (2) ReleasedCholyl-Gly-Gabapentin (9a) NR Cholyl-Phe-Gabapentin (9g)  4Cholyl-Tyr-Gabapentin (9h) 40NR = Not released

Example 6 Sustained Release of Gabapentin (2) from Cholyl-Phe-Gabapentin(9) Following Oral Administration to Rats

The pharmacokinetics of the prodrug Cholyl-Phe-Gabapentin (9g) wereexamined in rats. Three groups of four male Sprague-Dawley rats (approx200 g) with jugular cannulae each received one of the followingtreatments: A) a single bolus intravenous injection of Gabapentin (25mg/kg, as a solution in water); B) a single oral dose of Gabapentin (25mg/kg, as a solution in water) administered by oral gavage; C) a singleoral dose of (9g) (103.5 mg/kg, as a solution in water) administered byoral gavage. Animals were fasted overnight prior to dosing and until 4hours post-dosing. Serial blood samples were obtained over 24 hoursfollowing dosing and blood was processed for plasma by centrifugation.Plasma samples were stored at −80° C. until analyzed.

Concentrations of (9g) or (2) in plasma samples were determined byLC/MS/MS as described above. Plasma (50 μL) was precipitated by additionof 100 mL of methanol and supernatent was injected directly onto theLC/MS/MS system. Following oral administration of Gabapentin,concentrations of Gabapentin in plasma reached a maximum at 1.3±0.5hours (T_(max)) and declined thereafter with a terminal half-life of3.0±1.3 hours. The oral bioavailability of Gabapentin was 87±18%.Following oral administration of Cholyl-Phe-Gabapentin (9g),concentrations of Gabapentin in plasma reached a maximum at ˜7.1 hourspost-dosing and declined thereafter with a terminal half-life of ˜5.1hours. Concentrations of released Gabapentin in plasma were sustainedbeyond 24 hours. These data indicate that prodrug Cholyl-Phe-Gabapentin(9g) is metabolized to Gabapentin (2) in vivo, and that a substantiallysustained release of Gabapentin was achieved following oraladministration of (9g) compared to the relatively rapid clearanceobserved for oral Gabapentin.

Example 7 Sustained Release of Gabapentin (2) from Cholyl-Gly-Gabapentin(9a) Following Oral Administration to Rats

Following oral administration of Cholyl-Gly-Gabapentin (9a) (90.4 mg/kg,as a solution in water) according to the protocol of Example 6 above,concentrations of Gabapentin in plasma reached a maximum at ˜8.0 hourspost-dosing and declined thereafter with a terminal half-life of ˜6.9hours. Concentrations of released Gabapentin in plasma were sustainedbeyond 24 hours. These data indicate that prodrug Cholyl-Gly-Gabapentin(9a) is metabolized to Gabapentin (2) in vivo, and that a substantiallysustained release of Gabapentin was achieved following oraladministration of (9a) compared to the relatively rapid clearanceobserved for oral Gabapentin.

Example 8 Sustained Release of Gabapentin (2) from Cholyl-Tyr-Gabapentin(9h) Following Oral Administration to Rats

Following oral administration of Cholyl-Tyr-Gabapentin (9h) (106 mg/kg,as a solution in water) according to the protocol of Example 6 above,concentrations of Gabapentin in plasma reached a maximum at ˜7.3 hourspost-dosing and declined thereafter with a terminal half-life of ˜4.5hours.

Concentrations of released Gabapentin in plasma were sustained beyond 24hours. These data indicate that prodrug Cholyl-Tyr-Gabapentin (9h) ismetabolized to Gabapentin (2) in vivo, and that a substantiallysustained release of Gabapentin was achieved following oraladministration of (9h) compared to the relatively rapid clearanceobserved for oral Gabapentin.

In view of the above disclosure, it is understood, of course, thatcombinations of substituents within the compounds of the presentinvention do not include any combination that is chemically impossibleor non-feasible as would be appreciated by one skilled in the art.

REFERENCES

-   Arya, P.; Burton, G. W. Bile acids for biological and chemical    applications and processes for the production thereof. U.S. Pat. No.    5,541,348, 1996.-   Baringhaus, K.-H.; Matter, H.; Stengelin, S.; Kramer, W. Substrate    specificity of the ileal and hepatic Na⁺/bile acid cotransporters of    the rabbit. II. A reliable 3D QSAR pharmacophore model for the ileal    Na⁺/bile acid cotransporter. J. Lipid Res. 1999, 40, 2158-2168.-   Bryans, J. S.; Wustrow, D. J. 3-Substituted GABA analogs with    central nervous system activity: a review. Med. Res. Rev. 1999,    19,149-177.-   Bundgaard, H. in Design of Prodrugs (Bundgaard, H. Ed.), Elsevier    Science B.V., 1985, pp. 1-92.-   Ho, N. F. H. Utilizing bile acid carrier mechanisms to enhance liver    and small intestine absorption. Ann. N. Y Acad. Sci. 1987, 507,    315-329.-   Jezyk, N.; Li, C.; Stewart, B. H.; Wu, X.; Bockbrader, H. N.;    Fleisher, D. Transport of pregabalin in rat intestine and Caco-2    monolayers. Pharm. Res. 1999, 16, 519-526.-   Kagedahl, M.; Swaan, P. W.; Redemann, C. T.; Tang, M.; Craik, C. S.;    Szoka, F. C.; Oie, S. Use of the intestinal bile acid transporter    for the uptake of cholic acid conjugates with HIV-1 protease    inhibitory activity. Pharm. Res. 1997, 14, 176-180.-   Kim, D.-C.; Harrison, A. W.; Ruwart, M. J.; Wilkinson, K. F.;    Fisher, J. F.; Hidalgo, I. J.; Borchardt, R. T. Evaluation of bile    acid transporter in enhancing intestinal permeability of    renin-inhibitory peptides. J. Drug Targeting 1993, 1, 347-359.-   Kramer, W.; Wess, G.; Schubert, G.; Bickel, M.; Girbig, F.; Gutjahr,    U.; Kowalewski, S.; Baringhaus, K.-H.; Enhsen, A.; Glombik, H.;    Mullner, S.; Neckermann, G.; Schulz, S.; Petzinger, E.    Liver-specific drug targeting by coupling to bile acids. J. Biol.    Chem. 1992, 267, 18598-18604.-   Kramer, W.; Wess, G.; Neckermann, G.; Schubert, G.; Fink, J.;    Girbig, F.; Gutjahr, U.; Kowalewski, S.; Baringhaus, K.-H.; Boger,    G.; Enhsen, A.; Falk, E.; Friedrich, M.; Glombik, H.; Hoffmann, A.;    Pittius, C.; Urmann, M. Intestinal absorption of peptides by    coupling to bile acids. J. Biol. Chem. 1994a, 269, 10621-10627.-   Kramer, W.; Wess, G.; Enhsen, A.; Bock, K.; Falk, E.; Hoffmann, A.;    Neckerman, G.; Gantz, D.; Schulz, S.; Nickau, L.; Petzinger, E.;    Turley, S.; Dietschy, J. M. Bile acid derived HMG-CoA reductase    inhibitors. Biochim. Biophys. Acta 1994b, 1227, 137-154.-   Kramer, W.; Wess, G. Modified bile acid conjugates, and their use as    pharmaceuticals. U.S. Pat. No. 5,462,933, 1995.-   Kramer, W.; Wess, G. Bile acid conjugates of proline hydroxylase    inhibitors. U.S. Pat. No. 5,646,272, 1997a.-   Kramer, W.; Wess, G. Bile acid derivatives, processes for their    preparation, and use as pharmaceuticals. U.S. Pat. No. 5,668,126,    1997b.-   Kramer, W.; Stengelin, S.; Baringhaus, K.-H.; Enhsen, A.; Heuer, H.;    Becker, W.; Corsiero, D.; Girbig, F.; Noll, R.; Weyland, C.    Substrate specificity of the ileal and hepatic Na⁺/bile acid    cotransporters of the rabbit. I. Transport studies with membrane    vesicles and cell lines expressing the cloned transporters. J. Lipid    Res. 1999, 40, 1604-1617.-   Kullak-Ublick, G. A.; Beuers, U.; Paumgartner, G. Hepatobiliary    transport. J. Hepatology 2000, 32 (Suppl. 1), 3-18.-   Mills, C. O; Iqbal, S.; Elias, E. Ileal absorption of    tyrosine-conjugated bile acids in Wistar rats. Biochim. Biophys.    Acta 1987, 926, 154-159.-   Navia, M. A.; Chaturvedi, P. R. Design principles for orally    bioavailable drugs. Drug Discovery Today 1996, 1, 179-189.-   Petzinger, E.; Nickau, L.; Horz, J. A.; Schulz, S.; Wess, G.;    Enhsen, A.; Falk, E.; Baringhaus, K.-H.; Glombik, H.; Hoffmann, A.;    Mullner, S.; Neckermann, G.; Kramer, W. Hepatobiliary transport of    hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors    conjugated with bile acids. Hepatology 1995, 22, 1801-1811.-   Reiner, A. Process for preparing ursodeoxycholic acid derivatives    and their inorganic and organic salts having therapeutic activity.    Eur. Patent 0 272 462 B1, 1992.-   Swaan, P. W.; Szoka, F. C.; Oie, S. Use of the intestinal and    hepatic bile acid transporters for drug delivery. Adv. Drug Delivery    Rev. 1996, 20, 59-82.-   Swaan, P. W.; Hillgren, K. M.; Szoka, F. C.; Oie, S. Enhanced    transepithelial transport of peptides by conjugation to cholic acid.    Bioconj. Chem. 1997, 8, 520-525.-   Tsuji, A.; Tamai, I. Carrier-mediated intestinal transport of drugs.    Pharm. Res. 1996, 13, 963-977.

Each of the above references is incorporated herein by reference in itsentirety.

1. A compound of formula (I):

wherein: R¹ and R² are independently hydrogen or hydroxy; X is Q^(x)-G-where: G is —O—, —C(O)O— or —NH—; Q^(x) is a group derived from a linearoligopeptide comprising a first moiety D and further comprising from 1to 3 amino acids, and wherein said group is cleavable from (I) underphysiological conditions; D is a drug containing at least one carboxylicacid group and at least one moiety selected from the group consisting ofa primary amino group, a secondary amino group or a hydroxyl group, withthe provisos that the drug is not a GABA analog; L-Dopa, an L-aromaticamino acid decarboxylase inhibitor, a catechol O-methyl transferaseinhibitor or derivatives thereof; a naturally occurring α-amino acid oran ester or carboxamide of a naturally occurring α-amino acid; apolypeptide derived from a linear oligopeptide containing at least 3α-amino acids; an oligonucleotide; a cyclophane derivative, adiethylenetriaminopentaacetate derivative, or paramagnetic ion chelatesthereof; 5-de-O-methylsporaricin; a bis-(2-chloroethyl)amine containingnitrogen mustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; or a steroid containing the carbon substructures of thefollowing formulae:

Z is a substituted alkyl group containing a moiety which is negativelycharged at physiological pH, which moiety is selected from the groupconsisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR⁶)(OH), —OP(O)(OR⁶)(OH),—OSO₃H and the like, and where R⁶ is selected from the group consistingof alkyl, substituted alkyl, aryl and substituted aryl

or a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1 wherein X is Q^(x)-G-, and wherein Q^(x) is of one of thefollowing two structures:-I_(i)-J_(j)-D-K_(k)—R⁴⁰ or-T_(t)-D-U_(u)—V_(v)—R⁴¹ wherein I is—[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—; J is—[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—; K is—[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—; T is—[C(O)—(CR⁶⁵R⁶⁶)_(g)—(CR⁶⁷R⁶⁸)_(h)—NR⁶⁹]—; U is—[C(O)—(CR⁷⁰R⁷¹)_(m)—(CR⁷²R⁷³)_(n)—NR⁷⁴]—; V is—[C(O)—(CR⁷⁵R⁷⁶)_(o)—(CR⁷⁷R⁷⁸)_(p)—NR⁷⁹]—; R⁴⁰ is —OH or —OR¹⁷; R⁴¹ is—H, —C(O)R¹⁷, or —C(O)OR¹⁷; R¹⁷ is alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; a, b, C, d, e,f, g, h, m, n, o and p are independently 0 or 1, where at least one of aand b is 1; at least one of c and d is 1; at least one of e and f is 1;at least one of g and h is 1; at least one of m and n is 1; at least oneof o and p is 1; i, j, k, t, u and v are independently 0 or 1, where atleast one of i, j and k is 1; at least one of t, u and v is 1; R⁵⁰ ishydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring; R⁵¹ is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁵¹ and R⁵² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R⁵¹ and R⁵³ together with the atoms to which theyare attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl orsubstituted heterocyclyl ring; R⁵² is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁵⁵ is hydrogen or R⁵⁵ and R⁵⁶,together with the atoms to which they are attached form a heterocyclylring; R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁵⁸ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁵⁸ and R⁵⁹ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁵⁹ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁶⁰ is hydrogen or R⁶⁰ and R⁶¹, together with the atoms towhich they are attached form a heterocyclyl ring; R⁶¹ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶¹ and R⁶² together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁶¹ and R⁶³ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁶² ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁶³ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁶³ and R⁶⁴ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁶⁵ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶⁵ and R⁶⁶ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁶⁵ and R⁶⁷ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁶⁶ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁶⁷ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁶⁷ and R⁶⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶⁸ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁶⁹ is hydrogenor R⁶⁹ and R⁶⁸ together with the atoms to which they are attached form aheterocyclyl ring; R⁷⁰ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁷⁰ and R⁷¹together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring,or R⁷⁰ and R⁷² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁷¹ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁷² is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁷² and R⁷³ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁷³ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁷⁴ is hydrogen or R⁷⁴ and R⁷³ together with the atoms towhich they are attached form a heterocyclyl ring; R⁷⁵ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁷⁵ and R⁷⁶ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁷⁵ and R⁷⁷ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁷⁶ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁷⁷ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁷⁷ and R⁷⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁷⁸ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; and R⁷⁹ ishydrogen or R⁷⁹ and R⁷⁸ together with the atoms to which they areattached form a heterocyclyl ring; wherein the bond between J_(j) orU_(u) and D and any amino acid to which it is attached is an amide orester bond.
 3. (canceled)
 4. The compound according to claim 1, whereinR¹ and R² are both —OH; R¹ is —OH and R² is hydrogen; R¹ is —OH and R²is hydrogen; R¹ is hydrogen and R² is —OH; R¹ is —OH and R² is —OH; orR¹ and R² are both hydrogen.
 5. The compound according to claim 2,wherein I, J, K, T, U and V are moieties derived from naturallyoccurring α-amino acids.
 6. (canceled)
 7. The compound according toclaim 5, wherein b, c, d, e, f, g, h, j, k, m, n, o and p are 0, andwherein a and i are
 1. 8. (canceled)
 9. (canceled)
 10. A compound offormula (II):

wherein: R¹ and R² are independently hydrogen or hydroxy; X is P^(x)-G-where: G is —O—, —C(O)O— or —NH—; P^(x) is a group derived from a linearoligopeptide comprising a first moiety D″ and further comprising from 1to 3 amino acids, and wherein said group is cleavable from (II) underphysiological conditions; D″ is a drug containing at least one moietyselected from the group consisting of a primary amino group, a secondaryamino group or a hydroxyl group, with the provisos that the drug is nota GABA analog; L-Dopa, an L-aromatic amino acid decarboxylase inhibitor,a catechol O-methyl transferase inhibitor or derivatives thereof; anaturally occurring α-amino acid or an ester or carboxamide of anaturally occurring α-amino acid; a polypeptide derived from a linearoligopeptide containing at least 3 α-amino acids; an oligonucleotide; acyclophane derivative, a diethylenetriaminopentaacetate derivative, orparamagnetic ion chelates thereof; histamine or tyramine;5-de-O-methylsporaricin; a bis-(2-chloroethyl)amine containing nitrogenmustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; fluvalinate; or a steroid containing the carbon substructuresof the following formulae:

Z is a substituted alkyl group containing a moiety which is negativelycharged at physiological pH, which moiety is selected from the groupconsisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR⁶)(OH), —OP(O)(OR⁶)(OH),—OSO₃H and the like, and where R⁶ is selected from the group consistingof alkyl, substituted alkyl, aryl and substituted aryl;

or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 10 wherein X is P^(x)-G-, G is —C(O)O—, and whereinP^(x) is of the following structure:-I_(i)-J_(j)-K_(k)-D″wherein I is—[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—; J is—[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—; K is—[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—; a, b, c, d, e and f areindependently 0 or 1, where at least one of a and b is 1; at least oneof c and d is 1; at least one of e and f is 1; i, j and k areindependently 0 or 1, where at least one of i, j and k is 1; R⁵⁰ ishydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring; R⁵¹ is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁵¹ and R⁵² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R⁵¹ and R⁵³ together with the atoms to which theyare attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl orsubstituted heterocyclyl ring; R⁵² is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁵⁵ is hydrogen or R⁵⁵ and R⁵⁶,together with the atoms to which they are attached form a heterocyclylring; R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁵⁸ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁵⁸ and R⁵⁹ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁵⁹ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁶⁰ is hydrogen or R⁶⁰ and R⁶¹, together with the atoms towhich they are attached form a heterocyclyl ring; R⁶¹ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶¹ and R⁶² together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁶¹ and R⁶³ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁶² ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁶³ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁶³ and R⁶⁴ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; wherein the bondbetween K_(k) and D” and any amino acid to which it is attached is anamide or ester bond.
 12. (canceled)
 13. The compound according to claim10, wherein R¹ and R² are both —OH; R¹ is —OH and R² is hydrogen; R¹ is—OH and R² is hydrogen; R¹ is hydrogen and R² is —OH; R¹ is —OH and R²is —OH; or R¹ and R² are both hydrogen.
 14. The compound according toclaim 11, wherein I, J and K are moieties derived from naturallyoccurring α-amino acids.
 15. (canceled)
 16. The compound according toclaim 14, wherein b, c, d, e, f, j and k are 0, and wherein a and iare
 1. 17. (canceled)
 18. A compound of formula (III):

wherein: R¹ and R² are independently hydrogen or hydroxy; X S^(x)G-where: G is —O—, or —NH—; S^(x) is a group derived from a linearoligopeptide comprising a first moiety D* and further comprising from 1to 3 amino acids, and wherein said group is cleavable from (III) underphysiological conditions; D* is a drug containing at least onecarboxylic acid group, with the provisos that the drug is not a GABAanalog; L-Dopa, an L-aromatic amino acid decarboxylase inhibitor, acatechol O-methyl transferase inhibitor or derivatives thereof; anaturally occurring α-amino acid or an ester or carboxamide of anaturally occurring α-amino acid; a polypeptide derived from a linearoligopeptide containing at least 3 α-amino acids; an oligonucleotide; acyclophane derivative, a diethylenetriaminopentaacetate derivative, orparamagnetic ion chelates thereof; 5-de-O-methylsporaricin; abis-(2-chloroethyl)amine containing nitrogen mustard; an HMG-CoAreductase inhibitor; a proline hydroxylase inhibitor; or a steroidcontaining the carbon substructures of the following formulae:

Z is a substituted alkyl group containing a moiety which is negativelycharged at physiological pH, which moiety is selected from the groupconsisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR⁶)(OH), —OP(O)(OR⁶)(OH),—OSO₃H and the like, and where R⁶ is selected from the group consistingof alkyl, substituted alkyl, aryl and substituted aryl.
 19. The compoundaccording to claim 18 wherein X is S^(x)-G-, and wherein S^(x) is of thefollowing structure:-T_(t)-U_(u)—V_(v)-D* wherein: T is—[C(O)—(CR⁶⁵R⁶⁶)_(g)—(CR⁶⁷R⁶⁸)_(h)—NR⁶⁹]—; U is—[C(O)—(CR⁷⁰R⁷¹)_(m)—(CR⁷²R⁷³)_(n)—NR⁷⁴]—; V is—[C(O)—(CR⁷⁵R⁷⁶)_(o)—(CR⁷⁷R⁷⁸)_(p)—NR⁷⁹]—; g, h, m, n, o and p areindependently 0 or 1, where at least one of g and h is 1; at least oneof m and n is 1; at least one of o and p is 1; t, u and v areindependently 0 or 1, where at least one of t, u and v is 1; R⁶⁵ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶⁵ and R⁶⁶ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶⁵ andR⁶⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶⁶ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁶⁷ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶⁷ and R⁶⁸ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁶⁸ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁶⁹ is hydrogen or R⁶⁹ and R⁶⁸ together with the atoms towhich they are attached form a heterocyclyl ring; R⁷⁰ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁷⁰ and R⁷¹ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁷⁰ and R⁷² togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁷¹ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁷² is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁷² and R⁷³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁷³ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁷⁴ is hydrogenor R⁷⁴ and R⁷³ together with the atoms to which they are attached form aheterocyclyl ring; R⁷⁵ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁷⁵ and R⁷⁶together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring,or R⁷⁵ and R⁷⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁷⁶ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁷⁷ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁷⁷ and R⁷⁸ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁷⁸ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; and R⁷⁹ is hydrogen or R⁷⁹ and R⁷⁸ together with the atomsto which they are attached form a heterocyclyl ring; wherein the bondbetween V_(v) and D* and any amino acid to which it is attached is anamide bond.
 20. The compound according to claim 18, wherein R¹ and R²are both —OH; R¹ is —OH and R² is hydrogen; R¹ is —OH and R² ishydrogen; R¹ is hydrogen and R² is —OH; R¹ is —OH and R² is —OH; or R¹and R² are both hydrogen.
 21. The compound according to claim 19,wherein T, U and V are moieties derived from naturally occurring α-aminoacids.
 22. The compound according to claim 19, wherein h, m, n, o, p, uand v are 0, and wherein g and t are
 1. 23. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compoundaccording to claims 1, 10 or 18.